Imidazoloindazole compounds as JAK inhibitors

Abstract

Compounds of formula (I): TIFF2024524214000147.tif3244 and pharmaceutically acceptable salts thereof, wherein A, W, X, Y and Z are defined herein. Compounds of formula (I) and pharmaceutically acceptable salts thereof are Janus kinase (JAK) inhibitors. Pharmaceutical compositions comprising such compounds, as well as methods of using such compounds to treat inflammatory and fibrotic diseases, including, for example, respiratory diseases, are also provided herein. Pharmaceutical compositions comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are also provided herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 202,811, filed June 25, 2021, which is incorporated by reference in its entirety herein.

[0002] Field Provided herein are compounds useful as Janus kinase (JAK) inhibitors. Also provided herein are pharmaceutical compositions comprising such compounds, as well as methods of using such compounds to treat inflammatory and fibrotic diseases, including, for example, respiratory diseases. [Background technology]

[0003] background Asthma is a chronic airway disease with no preventative or curative drugs. The disease is characterized by airway inflammation, fibrosis, hyperresponsiveness, and remodeling, all of which contribute to airflow limitation. An estimated 300 million people worldwide suffer from asthma, and the number of asthmatics is estimated to increase by over 100 million by 2025. In the United States, asthma afflicts approximately 6%-8% of the population, making it one of the most common chronic diseases in the country. Although most patients are able to control their asthma symptoms using inhaled corticosteroids, which may be combined with leukotriene modifiers and / or long-acting beta-agonists, there is a subset of patients with severe asthma who are not controlled by traditional medications. Severe persistent asthma is defined as disease that remains uncontrolled with high doses of inhaled corticosteroids. Patients with severe asthma are estimated to represent approximately 5% of all asthma patients, but are at high risk of morbidity and mortality, leading to a disproportionate distribution of healthcare resource utilization among asthma patients. Novel therapeutics to treat these patients remain needed.

[0004] Cytokines are intercellular signaling molecules that include chemokines, interferons, interleukins, lymphokines and tumor necrosis factors. Cytokines are important for normal cell proliferation and immune regulation, but also drive immune-mediated diseases and contribute to the proliferation of malignant cells. Elevated levels of many cytokines have been implicated in the pathology of asthmatic inflammation. For example, antibody-based therapeutics targeting interleukin (IL)-5 and 13 have been shown to confer clinical benefit in a subset of patients with severe asthma. Of the cytokines involved in asthmatic inflammation, many act through signaling pathways that depend on the Janus family of tyrosine kinases (JAKs), which signal through the signal transduction and activator of transcription (STAT) family of transcription factors. Cytokines involved in asthmatic inflammation that signal through the JAK-STAT pathway include IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon-γ (IFNγ), and granulocyte-macrophage colony-stimulating factor (GM-CSF).

[0005] The JAK family includes four members, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Binding of cytokines to JAK-dependent cytokine receptors induces receptor dimerization leading to phosphorylation of tyrosine residues on the JAK kinase, resulting in JAK activation. The phosphorylated JAKs then dimerize, internalize into the cell nucleus, and bind and phosphorylate various STAT proteins that directly regulate gene transcription, among other effects, resulting in downstream effects related to inflammatory diseases. JAKs typically associate with cytokine receptors in pairs as homodimers or heterodimers. Certain cytokines are associated with specific JAK pairings. Each of the four members of the JAK family is involved in the signaling of at least one of the cytokines associated with asthmatic inflammation. As a result, chemical inhibitors with panactivity against all members of the JAK family could modulate a wide range of pro-inflammatory pathways that contribute to the development of severe asthma. However, the broad anti-inflammatory effects of such inhibitors may suppress normal immune cell function, potentially increasing the risk of infection. Evidence of increased risk of infection was seen with the JAK inhibitor tofacitinib, which is orally administered to treat rheumatoid arthritis. In asthma, inflammation is localized to the airways. In addition to asthma, airway inflammation is characteristic of other respiratory diseases. Chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pneumonitis, interstitial lung disease (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, and sarcoidosis are also airway diseases whose pathophysiology is thought to be related to JAK signaling cytokines. Local administration of JAK inhibitors to the lungs by inhalation offers the potential to be therapeutically effective by delivering potent anti-cytokine agents directly to the site of action, limiting systemic exposure and therefore the potential for deleterious systemic immunosuppression. There remains a need for potent JAK inhibitors suitable for local administration to the lungs to treat respiratory diseases.

[0006] JAK signaling cytokines also play a major role in the activation of T cells, a subtype of immune cells central to many immune processes. Pathological T cell activation is important in the pathogenesis of multiple respiratory diseases. Autoreactive T cells play a role in bronchiolitis obliterans organizing pneumonia (also called COS). Similar to COS, the pathogenesis of lung transplant rejection is associated with aberrant T cell activation of recipient T cells by the transplanted donor lung. Lung transplant rejection can occur early as primary graft dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR) or lymphocytic bronchiolitis (LB), or it can occur several years after lung transplantation as chronic transplant pulmonary dysfunction (CLAD). CLAD was previously known as bronchiolitis obliterans (BO) but is now considered a syndrome that can have different pathological manifestations including BO, restrictive CLAD (rCLAD or RAS) and neutrophilic allograft dysfunction. Chronic transplant pulmonary dysfunction (CLAD) is a major challenge in the long-term management of lung transplant recipients, as it gradually causes the transplanted lung to lose functionality (Gauthier et al., Curr. Transplant. Rep., 2016, 3(3), 185-191). CLAD is poorly responsive to treatment, and therefore there is still a need for effective compounds that can prevent or treat this condition. Several JAK-dependent cytokines, such as IFNγ and IL-5, are upregulated in CLAD and lung transplant rejection (Berastegui et al., Clin. Transplant. 2017, 31, e12898). Furthermore, high pulmonary levels of CXCR3 chemokines, such as CXCL9 and CXCL10, downstream of JAK-dependent IFN signaling, are associated with worse outcomes in lung transplant patients (Shino et al., PLOS One, 2017, 12(7), e0180281). Systemic JAK inhibition has been shown to be effective in renal transplant rejection (Vicenti et al., American Journal of Transplantation, 2012, 12, 2446-56). Therefore, JAK inhibitors may be effective in treating or preventing lung transplant rejection and CLAD.T cell activation events similar to those described as the basis of lung transplant rejection are also thought to be the primary driver of pulmonary graft-versus-host disease (GVHD) that can occur after hematopoietic stem cell transplantation. Like CLAD, pulmonary GVHD is a chronic progressive condition with extremely poor outcomes and currently no approved treatments. A retrospective multicenter survey study of 95 patients with steroid-refractory acute or chronic GVHD who received the systemic JAK inhibitor ruxolitinib as salvage therapy demonstrated complete or partial responses to ruxolitinib in the majority of patients, including those with pulmonary GVHD (Zeiser et al., Leukemia, 2015, 29, 10, 2062-68). Because systemic JAK inhibition is associated with severe adverse events and a small therapeutic index, there remains a need for inhaled lung-directed nonsystemic JAK inhibitors to prevent and / or treat lung transplant rejection or pulmonary GVHD. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Gauthier et al., Curr. Transplant. Rep., 2016, 3(3), 185-191 [Non-Patent Document 2] Berastegui et al., Clin. Transplant. 2017, 31, e12898 [Non-Patent Document 3] Shino et al., PLOS One, 2017, 12(7), e0180281 [Non-Patent Document 4] Vicenti et al., American Journal of Transplantation, 2012, 12, 2446-56 [Non-Patent Document 5] Zeiser et al., Leukemia, 2015, 29, 10, 2062-68 Summary of the Invention [Means for solving the problem]

[0008] overview Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof is provided herein. [In the formula, W is H, -C 1~6 is alkyl or halogen; X is H or F; Y is H, -CH3, or F; Z is -CH2CH3, -CF2CH3, or -CH2CF3; A has a double bond, -C 1~6 Alkyl, -COR 1 , -SO2R 1 , -CO2R 2 , -CONR 2 R 3 , -SO2NR 2 R 3 is a 4- to 7-membered monocyclic heterocyclic group optionally substituted with 1 to 8 substituents independently selected from the group consisting of aryl, heteroaryl, 3- to 7-membered cycloalkyl, and 4- to 7-membered heterocyclic groups; -C 1~6 Alkyl is -C 1~6 Alkyl, -NR 2 R 3 , -CN, -CO2R 2 , -CONR 2 R 3 , -OH, -SO2NR 2 R 3 , -SO2-C 1~6 Alkyl, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 2 R 3 , -NR 2 C(O)-R 1 , -NR 2 C(O)2R 3 , -NR 2 -C(O)NR 3 R 4 , -OCO2R 3 , -NR 2 SO2-C1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl, and 4- to 7-membered heterocyclic groups, wherein the 3- to 7-membered cycloalkyl and 4- to 7-membered heterocyclic groups are oxo, -C 1~6 Alkyl, -CN, -COR 5 , -CONR 5 R 6 , -OH, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 5 R 6 , -OC(O)NR 5 R 6 , -NR 5 C(O)-C 1~6 Alkyl, -NR 5 C(O)2R 6 , -NR 5 -C(O)NR 6 R 7 , -C 1~6 Alkyl-OR 5 , -C 1~6 Alkyl-NR 5 R 6 , and -C 1~6 Alkyl-CO2R 5 and wherein the aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -CN, -COR 8 , -CONR 8 R 9 , -OH, -SH, -C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 8 R 9 , -OC(O)NR 8 R 9 , -OCO2R 8 , -NR 8 C(O)-C 1~6 Alkyl, -NR 8 C(O)2R 9 , -NR 8 -C(O)NR 9 R 10 , -C 1~6 Alkyl-OR8 , -C 1~6 Alkyl-NR 8 R 9 , and -C 1~6 Alkyl-CO2R 8 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of A is optionally fused or bridged with a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group; Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group is a spiro 3- to 7-membered cycloalkyl group, a spiro 4- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, -C 1~6 Alkyl, -CF3, oxo, -CN, -CO2R 11 , -CONR 11 R 12 , -OH, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 11 R 12 , -OC(O)NR 11 R 12 , -NR 11 C(O)-C 1~6 Alkyl, -NR 11 C(O)2R 12 , -NR 11 -C(O)NR 12 R 13 , -OCO2R 12 , -NR 11 -SO2-C 1~6 Alkyl, -C 1~6 Alkyl-OR 11 , -C 1~6 Alkyl-NR 11 R 12 , and -C 1~6 Alkyl-CO2R 11 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of Each R 1 is an aryl, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, and -C 1~6 alkyl, -C 1~6 Alkyl is -NR a R b, -OH, -OC 1~6 Alkyl, -OC 1~6 Alkyl-NR a R b , aryl, heteroaryl, and 4- to 7-membered heterocyclic group, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -NR 14 R 15 , -OH, -C 1~6 Alkyl, -CN, -COR 14 , -CONR 14 R 15 , -SO2NR 14 R 15 , -SO2-C 1~6 Alkyl, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 14 R 15 , -NR 14 C(O)-C 1~6 Alkyl, -NR 14 C(O)2R 15 , -NR 14 -C(O)NR 15 R 16 , -OCO2R 14 and -NR 14 SO2-C 1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, Each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 、 R 9 , R 10 , R 11 , R 12 , R 13 , R a , and R b , H, C 1~6 Alkyl, and -C 1~6 Alkyl-OR 14 are independently selected from the group consisting of: -CONR 2 R 3 and -SO2NR 2 R 3 In R 2 and R 3 are combined as necessary to form -NR c R d , -OH, -C 1~6 Alkyl, -CN, -COR 14 , -CONR 14 R 15 , -SO2NR 14 R 15 , -SO2-C 1~6 Alkyl, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 14 R 15 , -NR 14 C(O)-C 1~6 Alkyl, -NR 14 C(O)2R 15 , -NR 14 -C(O)NR 15 R 16 , -OCO2R 14 , and -NR 14 SO2-C 1~6 forming a 4- to 7-membered heterocyclic group optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl; Each R c , R d , R 14 , R 15 , and R 16 H and C 1~6 alkyl.

[0009] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, X is H or F; Y is H or F; A has a double bond, -C1~6 Alkyl, -COR 1 , -SO2R 1 , -CO2R 2 , -CONR 2 R 3 , -SO2NR 2 R 3 a 4- to 7-membered monocyclic heterocyclic group optionally substituted with 1 to 8 substituents independently selected from the group consisting of a 3- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group; -C 1~6 Alkyl is -C 1~6 Alkyl, -NR 2 R 3 , -CN, -CO2R 2 , -CONR 2 R 3 , -OH, -SO2NR 2 R 3 , -SO2-C 1~6 Alkyl, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 2 R 3 , -NR 2 C(O)-C 1~6 Alkyl, -NR 2 C(O)2R 3 , -NR 2 -C(O)NR 3 R 4 , -OCO2R 3 , -NR 2 SO2-C 1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl, and 4- to 7-membered heterocyclic groups, wherein the 3- to 7-membered cycloalkyl and 4- to 7-membered heterocyclic groups are oxo, -C 1~6 Alkyl, -CN, -COR 5 , -CONR 5 R 6 , -OH, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 5 R 6 , -OC(O)NR 5 R 6 , -NR5 C(O)-C 1~6 Alkyl, -NR 5 C(O)2R 6 , -NR 5 -C(O)NR 6 R 7 , -C 1~6 Alkyl-OR 5 , -C 1~6 Alkyl-NR 5 R 6 , and -C 1~6 Alkyl-CO2R 5 and wherein the aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -CN, -COR 8 , -CONR 8 R 9 , -OH, -SH, -C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 8 R 9 , -OC(O)NR 8 R 9 , -OCO2R 8 , -NR 8 C(O)-C 1~6 Alkyl, -NR 8 C(O)2R 9 , -NR 8 -C(O)NR 9 R 10 , -C 1~6 Alkyl-OR 8 , -C 1~6 Alkyl-NR 8 R 9 , and -C 1~6 Alkyl-CO2R 8 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of A is optionally fused or bridged with a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group; Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group is a spiro 3- to 7-membered cycloalkyl group, a spiro 4- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, -C 1~6Alkyl, oxo, -CN, -COR 11 , -CONR 11 R 12 , -OH, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 11 R 12 , -OC(O)NR 11 R 12 , -NR 11 C(O)-C 1~6 Alkyl, -NR 11 C(O)2R 12 , -NR 11 -C(O)NR 12 R 13 , -OCO2R 12 , -NR 11 -SO2-C 1~6 Alkyl, -C 1~6 Alkyl-OR 11 , -C 1~6 Alkyl-NR 11 R 12 , and -C 1~6 Alkyl-CO2R 11 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of Each R 1 is an aryl, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, and -C 1~6 alkyl, -C 1~6 Alkyl is -NR a R b , -OH, -OC 1~6 Each of the aryl, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclic and heteroaryl groups is optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, aryl- ... 14 R 15 , -OH, -C 1~6 Alkyl, -CN, -COR 14 , -CONR 14 R 15 , -SO2NR 14 R 15 , -SO2-C 1~6 Alkyl, -SH, -OC1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 14 R 15 , -NR 14 C(O)-C 1~6 Alkyl, -NR 14 C(O)2R 15 , -NR 14 -C(O)NR 15 R 16 , -OCO2R 14 and -NR 14 SO2-C 1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, Each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 、 R 9 , R 10 , R 11 , R 12 , R 13 , R a , and R b H and C 1~6 independently selected from the group consisting of alkyl, -CONR 2 R 3 and -SO2NR 2 R 3 In R 2 and R 3 are combined as necessary to form -NR c R d , -OH, -C 1~6 Alkyl, -CN, -COR 14 , -CONR 14 R 15 , -SO2NR 14 R 15 , -SO2-C 1~6 Alkyl, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 14 R 15 , -NR 14 C(O)-C 1~6Alkyl, -NR 14 C(O)2R 15 , -NR 14 -C(O)NR 15 R 16 , -OCO2R 14 , and -NR 14 SO2-C 1~6 forming a 4- to 7-membered heterocyclic group optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl; Each R c , R d , R 14 , R 15 , and R 16 H and C 1~6 alkyl.

[0010] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0011] Also provided herein is a method of treating respiratory diseases, particularly asthma and lung rejection, in a mammal (e.g., a human), comprising the step of administering to the mammal (or human) a compound of Formula (I) or Formula (II), or a pharma- ceutically acceptable salt thereof.

[0012] The disclosure also provides compounds of Formula (I) or Formula (II), or pharma- ceutically acceptable salts thereof, for use in medical therapy, and the use of such compounds in the manufacture of a formulation or medicament for treating a respiratory disease in a mammal (e.g., a human). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein A, W, X, Y and Z are as defined herein.

[0014] In some embodiments, W is H. In some embodiments, W is -C (including, for example, methyl, ethyl, n-propyl, and isopropyl). 1~6 In some embodiments, W is alkyl. In some embodiments, W is halogen (including, for example, fluoro, chloro, and bromo). In some embodiments, W is H, -CH3, or bromo.

[0015] In some embodiments, X is H. In some embodiments, X is F.

[0016] In some embodiments, Y is H. In some embodiments, Y is F. In some embodiments, Y is -CH3. In some embodiments, Y is H or F.

[0017] In some embodiments, Z is -CH2CH3. In some embodiments, Z is -CF2CH3. In some embodiments, Z is -CH2CF3.

[0018] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, X is H or F; Y is H or F; A has a double bond, -C 1~6 Alkyl, -COR 1 , -SO2R 1 , -CO2R 2 , -CONR 2 R 3 , -SO2NR 2 R 3 a 4- to 7-membered monocyclic heterocyclic group optionally substituted with 1 to 8 substituents independently selected from the group consisting of a 3- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group; -C 1~6Alkyl is -C 1~6 Alkyl, -NR 2 R 3 , -CN, -CO2R 2 , -CONR 2 R 3 , -OH, -SO2NR 2 R 3 , -SO2-C 1~6 Alkyl, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 2 R 3 , -NR 2 C(O)-C 1~6 Alkyl, -NR 2 C(O)2R 3 , -NR 2 -C(O)NR 3 R 4 , -OCO2R 3 , -NR 2 SO2-C 1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl, and 4- to 7-membered heterocyclic groups, wherein the 3- to 7-membered cycloalkyl and 4- to 7-membered heterocyclic groups are oxo, -C 1~6 Alkyl, -CN, -COR 5 , -CONR 5 R 6 , -OH, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 5 R 6 , -OC(O)NR 5 R 6 , -NR 5 C(O)-C 1~6 Alkyl, -NR 5 C(O)2R 6 , -NR 5 -C(O)NR 6 R 7 , -C 1~6 Alkyl-OR 5 , -C 1~6 Alkyl-NR 5 R 6 , and -C 1~6 Alkyl-CO2R 5and wherein the aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -CN, -COR 8 , -CONR 8 R 9 , -OH, -SH, -C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 8 R 9 , -OC(O)NR 8 R 9 , -OCO2R 8 , -NR 8 C(O)-C 1~6 Alkyl, -NR 8 C(O)2R 9 , -NR 8 -C(O)NR 9 R 10 , -C 1~6 Alkyl-OR 8 , -C 1~6 Alkyl-NR 8 R 9 , and -C 1~6 Alkyl-CO2R 8 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of A is optionally fused or bridged with a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group; Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group is a spiro 3- to 7-membered cycloalkyl group, a spiro 4- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, -C 1~6 Alkyl, oxo, -CN, -COR 11 , -CONR 11 R 12 , -OH, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 11 R 12 , -OC(O)NR 11 R 12 , -NR 11 C(O)-C 1~6 Alkyl, -NR 11 C(O)2R 12 , -NR11 -C(O)NR 12 R 13 , -OCO2R 12 , -NR 11 -SO2-C 1~6 Alkyl, -C 1~6 Alkyl-OR 11 , -C 1~6 Alkyl-NR 11 R 12 , and -C 1~6 Alkyl-CO2R 11 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of Each R 1 is an aryl, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, and -C 1~6 alkyl, -C 1~6 Alkyl is -NR a R b , -OH, -OC 1~6 Each of the aryl, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclic and heteroaryl groups is optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, aryl- ... 14 R 15 , -OH, -C 1~6 Alkyl, -CN, -COR 14 , -CONR 14 R 15 , -SO2NR 14 R 15 , -SO2-C 1~6 Alkyl, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 14 R 15 , -NR 14 C(O)-C 1~6 Alkyl, -NR 14 C(O)2R 15 , -NR 14 -C(O)NR 15 R 16 , -OCO2R 14 and -NR 14 SO2-C 1~6and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, Each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 、 R 9 , R 10 , R 11 , R 12 , R 13 , R a , and R b H and C 1~6 independently selected from the group consisting of alkyl, -CONR 2 R 3 and -SO2NR 2 R 3 In R 2 and R 3 are combined as necessary to form -NR c R d , -OH, -C 1~6 Alkyl, -CN, -COR 14 , -CONR 14 R 15 , -SO2NR 14 R 15 , -SO2-C 1~6 Alkyl, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 14 R 15 , -NR 14 C(O)-C 1~6 Alkyl, -NR 14 C(O)2R 15 , -NR 14 -C(O)NR 15 R 16 , -OCO2R 14 , and -NR 14 SO2-C 1~6 forming a 4- to 7-membered heterocyclic group optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl; Each R c , R d , R14 , R 15 , and R 16 H and C 1~6 alkyl.

[0019] In some embodiments, X is H or F and Y is H or F; A has a double bond, C 1~6 Alkyl, -COR 1 , SO2R 1 , -CO2R 2 , -CONR 2 R 3 , SO2NR 2 R 3 , a 3- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group; -C 1~6 Alkyl is -C 1~6 Alkyl, -NR 2 R 3 , -CONR 2 R 3 , -OH, -SO2NR 2 R 3 , -SO2-C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 2 C(O)-C 1~6 Alkyl, -NR 2 SO2-C 1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl, and 4- to 7-membered heterocyclic groups, wherein the 3- to 7-membered cycloalkyl and 4- to 7-membered heterocyclic groups are oxo, -C 1~6 and -OH, and aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -CN, -COR 8 , -CONR 8 R 9 , O.H., S.H., C. 1~6 Alkyl, -OC 1~6Alkyl, -SC 1~6 Alkyl, -NR 8 R 9 , -OC(O)NR 8 R 9 , -NR 8 C(O)-C 1~6 Alkyl, -NR 8 C(O)2R 9 , -NR 8 -C(O)NR 9 R 10 , -OCO2R 8 , -C 1~6 Alkyl-OR 8 , -C 1~6 Alkyl-NR 8 R 9 , and -C 1~6 Alkyl-CO2R 8 and optionally substituted with 1 to 3 substituents independently selected from the group consisting of A is optionally bridged with a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group; Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group is -C 1~6 optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, oxo, and -OH; Each R 1 is phenyl, a 4- to 6-membered heterocyclic group, and -C 1~6 alkyl, -C 1~6 Alkyl is -NR a R b , -OH, and phenyl; Each R 2 , R 3 , R 8 、 R 9 , R 10 , R a , and R b H and C 1~6 independently selected from the group consisting of alkyl, -CONR 2 R 3 and -SO2NR 2 R3 In R 2 and R 3 Together, as necessary, NR c R d forming an optionally substituted 4- to 7-membered heterocyclic group; Each R c and R d H and C 1~6 alkyl.

[0020] In some embodiments, A is [ka] is selected from the group consisting of Each of these is -CO2R y , -CONR y R z , and -C 1~6 1 to 3 R independently selected from the group consisting of alkyl x with -C 1~6 Alkyl is -CN, -OH, -OC 1~6 Alkyl, -COR y , and -CONR y R z and optionally substituted with 1 to 5 substituents independently selected from the group consisting of R is H, -C 1~6 Alkyl, -COR 1 , -SO2R 1 , -CO2R 2 , -CONR 2 R 3 , -SO2NR 2 R 3 , a 3- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group; C 1~6 Alkyl is -C 1~6 Alkyl, -NR 2 R 3 , -CN, -CO2R 2 , -CONR 2 R 3 , OH, -SO2NR 2 R3 , SO2-C 1~6 Alkyl, SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 2 R 3 , -NR 2 C(O)-C 1~6 Alkyl, -NR 2 C(O)2R 3 , -NR 2 -C(O)NR 3 R 4 , -OCO2R 2 , -NR 2 SO2-C 1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl, and 4- to 7-membered heterocyclic groups, wherein the 3- to 7-membered cycloalkyl and 4- to 7-membered heterocyclic groups are oxo, -C 1~6 Alkyl, -CN, -COR 5 , -CONR 5 R 6 , -OH, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 5 R 6 , -OC(O)NR 5 R 6 , -NR 5 C(O)-C 1~6 Alkyl, -NR 5 C(O)2R 6 , -NR 5 -C(O)NR 6 R 7 , -OCO2R 5 , -C 1~6 Alkyl-OR 5 , -C 1~6 Alkyl-NR 5 R 6 , and -C 1~6 Alkyl-CO2R 5 and wherein the aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -CN, -COR 8 , -CONR 8 R 9, -OH, -SH, -C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 8 R 9 , -OC(O)NR 8 R 9 , -NR 8 C(O)-C 1~6 Alkyl, -NR 8 C(O)2R 9 , -NR 8 -C(O)NR 9 R 10 , -OCO2R 8 , -C 1~6 Alkyl-OR 8 , -C 1~6 Alkyl-NR 8 R 9 , and -C 1~6 Alkyl-CO2R 8 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group is a spiro 3- to 7-membered cycloalkyl group, a spiro 4- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, -C 1~6 Alkyl, oxo, -CN, -COR 11 , -CONR 11 R 12 , -OH, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 11 R 12 , -OC(O)NR 11 R 12 , -NR 11 C(O)-C 1~6 Alkyl, -NR 11 C(O)2R 12 , -NR 11 -C(O)NR 12 R 13 , -OCO2R 11 , -NR 11 -SO2-C 1~6 Alkyl, -C 1~6 Alkyl-OR 11 , -C 1~6 Alkyl-NR11 R 12 , and -C 1~6 Alkyl-CO2R 11 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of Each R 1 is an aryl, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, and -C 1~6 alkyl, -C 1~6 Alkyl is -NR a R b , -OH, -OC 1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl, each of which is -NR 14 R 15 , -OH, -C 1~6 Alkyl, -CN, -COR 14 , -CONR 14 R 15 , -SO2NR 14 R 15 , -SO2-C 1~6 Alkyl, -SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 14 R 15 , -NR 14 C(O)-C 1~6 Alkyl, -NR 14 C(O)2R 15 , -NR 14 -C(O)NR 15 R 16 , -OCO2R 14 , and -NR 14 SO2-C 1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, Each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 、 R 9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R a , R b , R c , R d , R y , and R z H and C 1~6 independently selected from the group consisting of alkyl, -CONR y R z In R y and R z Together, as necessary, NR c R d , OH, -C 1~6 Alkyl, CN, -CO2R 14 , -CONR 14 R 15 , -SO2NR 14 R 15 , SO2-C 1~6 Alkyl, SH, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -OC(O)NR 14 R 15 , -NR 14 C(O)-C 1~6 Alkyl, -NR 14 C(O)2R 15 , -NR 14 -C(O)NR 15 R 16 , -OCO2R 14 , and -NR 14 SO2-C 1~6 and forming a 4- to 7-membered heterocyclic group optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl.

[0021] In some embodiments, A is [ka] is selected from the group consisting of Each of these has 1 to 3 R xare substituted as necessary, and each R x are independently -OH, -OC 1~3 Alkyl, -CN, -CO2-C 1~3 Alkyl, and -CONR y R z -C, which is substituted as necessary 1~3 is alkyl, R y and R z are respectively, C 1~3 alkyl; R y and R z Together, as necessary, NR c R d and R c and R d are H and C, respectively. 1~3 alkyl.

[0022] In some embodiments, each R x are Me, -CH2OH, -CH2OMe, -CH2CN, -CH2CONMe2, -CH2CO2Me, -CO2Me, and [ka] are independently selected from the group consisting of:

[0023] In some embodiments, R is H, -C 1~6 Alkyl, -COR 1 , -SO2R 1 , -CO2R 2 , -CONR 2 R 3 , -SO2NR 2 R 3 , a 3- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group; -C 1~6 Alkyl is -C 1~6 Alkyl, -NR 2 R 3 , -CONR 2 R 3 , -OH, -SO2NR 2 R3 , -SO2-C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 2 C(O)-C 1~6 Alkyl, -NR 2 SO2-C 1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl, and 4- to 7-membered heterocyclic groups, wherein the 3- to 7-membered cycloalkyl and 4- to 7-membered heterocyclic groups are oxo, -C 1~6 and -OH, and aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -CN, -COR 8 , -CONR 8 R 9 , O.H., S.H., C. 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 8 R 9 , -OC(O)NR 8 R 9 , -NR 8 C(O)-C 1~6 Alkyl, -NR 8 C(O)2-C 1~6 Alkyl, -NR 8 -C(O)NR 9 R 10 , -OCO2R 8 , -C 1~6 Alkyl-OR 8 , -C 1~6 Alkyl-NR 8 R 9 , and -C 1~6 Alkyl-CO2R 8 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group is -C 1~6 optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, oxo, and -OH; Each R 1is an aryl, a 4- to 7-membered heterocyclic group, and -C 1~6 alkyl, -C 1~6 Alkyl is -NR a R b , -OH, and aryl; Each R 2 , R 3 , R 8 、 R 9 , R 10 , R a , and R b H and C 1~6 alkyl.

[0024] In some embodiments, R is H, -C 1~6 Alkyl, -COR 1 , -SO2R 1 , -CO2R 2 , -CONR 2 R 3 , -SO2NR 2 R 3 , a 4- to 6-membered cycloalkyl group, and a 4- to 6-membered heterocyclic group; -C 1~6 Alkyl is -NR 2 R 3 , -CONR 2 R 3 , -OH, -SO2NR 2 R 3 , -SO2-C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 2 C(O)-C 1~6 Alkyl, -NR 2 SO2-C 1~6optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, phenyl, 5-membered heteroaryl, 4- to 6-membered cycloalkyl, and 4- to 6-membered heterocyclic groups, and the 4- to 6-membered cycloalkyl and 4- to 6-membered heterocyclic groups are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo and -OH; The 4- to 6-membered cycloalkyl group and the 4- to 6-membered heterocyclic group are each represented by -C 1~6 optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, oxo, and -OH; Each R 1 is phenyl, a 4- to 6-membered heterocyclic group, and -C 1~6 alkyl, -C 1~6 Alkyl is -NR a R b , -OH, and phenyl; Each R 2 , R 3 , R a , and R b H and C 1~6 alkyl.

[0025] In some embodiments, Y is H and A is [ka] is selected from the group consisting of Each of these has 1 to 3 R x are substituted as necessary, and each R x are independently -OH, -OC 1~3 Alkyl, -CN, -CO2-C 1~3 Alkyl, and -CONR y R z -C, which is substituted as necessary 1~3 is alkyl, R y and R z are respectively, C 1~3 alkyl; R y and Rz Together, as necessary, NR c R d and R c and R d are H and C, respectively. 1~3 independently selected from the group consisting of alkyl, R is H, -C 1~6 Alkyl, -COR 1 , -SO2R 1 , -CO2R 2 , -CONR 2 R 3 , -SO2NR 2 R 3 , a 3- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group; -C 1~6 Alkyl is -C 1~6 Alkyl, -NR 2 R 3 , -CONR 2 R 3 , -OH, -SO2NR 2 R 3 , -SO2-C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 2 C(O)-C 1~6 Alkyl, -NR 2 SO2-C 1~6 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl, and 4- to 7-membered heterocyclic groups, wherein the 3- to 7-membered cycloalkyl and 4- to 7-membered heterocyclic groups are oxo, -C 1~6 and -OH, and aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -CN, -COR 8 , -CONR 8 R 9 , O.H., S.H., C. 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 8 R9 , -OC(O)NR 8 R 9 , -NR 8 C(O)-C 1~6 Alkyl, -NR 8 C(O)2-C 1~6 Alkyl, -NR 8 -C(O)NR 9 R 10 , -OCO2R 8 , -C 1~6 Alkyl-OR 8 , -C 1~6 Alkyl-NR 8 R 9 , and -C 1~6 Alkyl-CO2R 8 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of The 3- to 7-membered cycloalkyl group and the 4- to 7-membered heterocyclic group are each represented by -C 1~6 optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, oxo, and -OH; Each R 1 is an aryl, a 4- to 7-membered heterocyclic group, and -C 1~6 alkyl, -C 1~6 Alkyl is -NR a R b , -OH, and aryl; Each R 2 , R 3 , R 8 、 R 9 , R 10 , R a , and R b H and C 1~6 alkyl.

[0026] In some embodiments, Y is H and A is [ka] is selected from the group consisting of These are Me, -CH2OH, -CH2OMe, -CH2CN, -CH2CONMe2, -CH2CO2Me, -CO2Me and [ka] R is independently selected from the group consisting of x where appropriate, R is H, -C 1~6 Alkyl, -COR 1 , -SO2R 1 , -CO2R 2 , -CONR 2 R 3 , -SO2NR 2 R 3 , a 4- to 6-membered cycloalkyl group, and a 4- to 6-membered heterocyclic group; -C 1~6 Alkyl is -NR 2 R 3 , -CONR 2 R 3 , -OH, -SO2NR 2 R 3 , -SO2-C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -NR 2 C(O)-C 1~6 Alkyl, -NR 2 SO2-C 1~6 optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, phenyl, 5-membered heteroaryl, 4- to 6-membered cycloalkyl, and 4- to 6-membered heterocyclic groups, and the 4- to 6-membered cycloalkyl and 4- to 6-membered heterocyclic groups are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo and -OH; The 4- to 6-membered cycloalkyl group and the 4- to 6-membered heterocyclic group are each represented by -C 1~6 optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, oxo, and -OH; Each R 1 is phenyl, a 4- to 6-membered heterocyclic group, and -C 1~6alkyl, -C 1~6 Alkyl is -NR a R b , -OH, and phenyl; Each R 2 , R 3 , R a , and R b H and C 1~6 alkyl.

[0027] In some embodiments, X is H. In some embodiments, X is F.

[0028] In some embodiments, Y is H. In some embodiments, Y is F.

[0029] Compounds of Formula 1: [ka] or a pharma- ceutically acceptable salt thereof are also provided herein.

[0030] Compound of Formula 2: [ka] or a pharma- ceutically acceptable salt thereof are also provided herein.

[0031] Compounds of formula 3: [ka] or a pharma- ceutically acceptable salt thereof are also provided herein.

[0032] In some embodiments, the compound of formula I is selected from the compounds having the chemical structure of any one of Examples 1-393, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula I is a compound having the chemical structure of any one of the compounds in Table 4 of the Examples section, or a pharma- ceutically acceptable salt thereof.

[0033] Chemical structures herein are named according to the IUPAC rules as implemented in ChemDraw software (PerkinElmer, Inc., Cambridge, Mass.).

[0034] Additionally, the imidazole moiety of the compounds of the present disclosure exists in tautomeric forms, and although structures have been shown or named in a particular form, it will be understood that the invention and disclosure encompasses those tautomeric forms as well.

[0035] The compounds of the present disclosure may contain one or more chiral centers, and therefore such compounds (and their intermediates) may exist as racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures, and the like. Chiral compounds depicted or named herein without a defined stereochemistry at a chiral center are intended to include any or all possible stereoisomeric variations at the undefined stereocenter unless otherwise indicated. The depiction or naming of a particular stereoisomer means that the indicated stereocenter has the designated stereochemistry, with the understanding that minor amounts of other stereoisomers may also be present, unless otherwise indicated. Provided, however, that the utility of the depicted or named compound is not diminished by the presence of another stereoisomer.

[0036] The compounds of the present disclosure may also contain some basic groups (e.g., amino groups) and therefore such compounds may exist as a free base or in various salt forms, such as monoprotonated salt forms, diprotonated salt forms, triprotonated salt forms, etc., or mixtures thereof. All such forms are included within the scope of the present invention and disclosure, unless otherwise indicated.

[0037] The present invention and disclosure also include isotopically labeled compounds of formula (I) or formula (II), i.e., compounds of formula (I) or formula (II) in which one or more atoms have been replaced or enriched with an atom having the same atomic number but an atomic mass different from the atomic mass predominant in nature. Examples of isotopes that may be incorporated into compounds of formula (I) include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O, and 18 Of particular interest are compounds of formula (I) or formula (II) enriched with tritium or carbon-14, which may be used, for example, in tissue distribution studies. Compounds of formula (I) or formula (II) enriched with deuterium, particularly at the site of metabolism, are also of particular interest, which are expected to have greater metabolic stability. Additionally, 11 C. 15 O and 13 Of particular interest are compounds of formula (I) or formula (II) enriched with positron-emitting isotopes such as N, which may be used, for example, in Positron Emission Tomography (PET) studies.

[0038] definition When describing this disclosure, including its various aspects and embodiments, the following terms have the following meanings unless otherwise indicated.

[0039] The term "alkyl" means a monovalent saturated hydrocarbon group which may be linear or branched or combinations thereof. Unless otherwise defined, such alkyl groups typically contain from 1 to 10 carbon atoms. Representative alkyl groups include, by way of example only, methyl (Me), ethyl (Et), n-propyl (n-Pr) or (nPr), isopropyl (i-Pr) or (iPr), n-butyl (n-Bu) or (nBu), sec-butyl, isobutyl, tert-butyl (t-Bu) or (tBu), n-pentyl, n-hexyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2-ethylbutyl, 2,2-dimethylpentyl, 2-propylpentyl, and the like.

[0040] When a specific number of carbon atoms is intended for a particular term, the number of carbon atoms will be indicated preceding the term. For example, "C 1~3 The term "alkyl" means an alkyl group having from one to three carbon atoms, the carbon atoms being present in any chemically permissible configuration, including linear or branched configurations.

[0041] The term "aryl" refers to an aromatic hydrocarbon group having a single ring (i.e., phenyl) or fused rings (i.e., naphthalene). Unless otherwise defined, such aryl groups typically contain from 6 to 10 carbon ring atoms. Representative aryl groups include, by way of example, phenyl (i.e., benzene ring), naphthyl (i.e., naphthalene ring), and the like. As used herein, the term aryl includes monovalent, divalent, or polyvalent aryl groups.

[0042] The term "cycloalkyl" means a monovalent saturated or partially unsaturated carbocyclic radical which may be monocyclic or polycyclic. Unless otherwise defined, such cycloalkyl groups typically contain from 3 to 10 carbon atoms. Representative cycloalkyl groups include, by way of example, cyclopropyl (cPr), cyclobutyl (cBu), cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.

[0043] The term "halo" or "halogen" means fluoro, chloro, bromo or iodo.

[0044] The term "heteroaryl" refers to an aromatic group (i.e., a heteroaromatic group) having a single ring or two fused rings and containing at least one heteroatom (typically 1-3 heteroatoms) selected from nitrogen, oxygen, or sulfur in the ring. Unless otherwise defined, such heteroaryl groups typically contain 1-9 carbon atoms and a total of 3-10 ring atoms. Representative heteroaryl groups include, by way of example, monovalent, divalent, or polyvalent species such as benzimidazole, benzofuran, benzothiazole, benzothiophene, furan, imidazole, indole, isoquinoline, isothiazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiazole, thiophene, triazole, triazine, and the like, where the point(s) of attachment are at any available carbon or nitrogen ring atom. As used herein, the term heteroaryl includes monovalent, divalent, or polyvalent heteroaryl groups.

[0045] The terms "heterocyclyl," "heterocycle," "heterocyclic," or "heterocyclic ring" refer to a monovalent saturated or partially unsaturated cyclic non-aromatic group having a total of 3 to 10 ring atoms, the ring containing 2 to 9 carbon ring atoms and 1 to 4 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocyclic groups can be monocyclic or polycyclic (i.e., fused or bridged). Representative heterocyclyl groups include, by way of example, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholyl, indolin-3-yl, 2-imidazolinyl, tetrahydropyranyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, quinuclidinyl, 7-azanorbornanyl, nortropanyl, and the like, where the point of attachment is at any available carbon or nitrogen ring atom. When the context makes the point of attachment of a heterocyclic group clear, such groups may alternatively be referred to as non-valent species, ie, pyrrolidine, piperidine, piperazine, imidazole, tetrahydropyran, and the like.

[0046] The term "pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a mammal, such as a patient or human (e.g., a salt that has acceptable mammalian safety for a given administration regimen). Representative pharmaceutically acceptable salts include salts of acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, edisylic acid, fumaric acid, gentisic acid, gluconic acid, glucoronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, nicotinic acid, nitric acid, orotic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and xinafoic acid.

[0047] The term "therapeutically effective amount" means an amount sufficient to effect treatment when administered to a patient in need of treatment.

[0048] The term "treat" or "treatment" means improving or inhibiting the medical condition, disease or disorder (e.g., a respiratory disease) being treated in a patient (e.g., a human), or alleviating the symptoms of the medical condition, disease or disorder.

[0049] The term "salt thereof" refers to a compound formed when a hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation. For example, the cation can be a protonated form of a compound of formula (I), i.e., one or more amino groups are protonated by an acid. Typically, the salt is a pharma-ceutically acceptable salt, although this is not necessary for salts of intermediate compounds that are not intended for administration to a patient.

[0050] General synthetic procedure The compounds of the present disclosure and their intermediates can be prepared according to the following general methods and procedures using commercially available or conventionally prepared starting materials and reagents. The substituents and variables (e.g., X, Y, A, etc.) used in the following schemes have the same meanings as defined elsewhere herein, unless otherwise indicated. In addition, compounds having acidic or basic atoms or functional groups can be used or prepared as salts, unless otherwise indicated (in some cases, the use of salts in certain reactions requires that the salts be converted to non-salt forms, e.g., free bases, using conventional procedures before carrying out the reaction).

[0051] Although certain embodiments of the present disclosure can be illustrated or described by the following procedures, one of ordinary skill in the art will recognize that other embodiments or aspects of the present disclosure can be prepared using such procedures, or by using other methods, reagents, and starting materials known to those of ordinary skill in the art. In particular, it will be recognized that the compounds of the present disclosure can be prepared by a variety of process routes that combine reactants in different orders to provide various intermediates on the way to producing the final product.

[0052] General methods for preparing the final compounds of the present disclosure are illustrated in the following schemes.

[0053] Compounds I-17, I-27, I-54 can be prepared as shown in the Examples section. The 7-des-fluoro analog of I-54 can be prepared using similar chemistry with appropriate reagents and starting materials. Suzuki Coupling [ka]

[0054] The starting material (I-17, I-27, I-54, or its 7-des-fluoro analogues) (1 equivalent) can be reacted with the boronic acid or ester of A (1-5 equivalents) by dissolving in a solvent such as 1,4-dioxane to provide a concentration of 0.05-1 mmol or about 0.15 mmol of starting material. A base such as sodium carbonate is dissolved in a solvent such as water (a volume equal to 1 / 10-2 the volume of 1,4-dioxane used or about 1 / 3 the volume of 1,4-dioxane used) and the resulting solution is added to the above solvent solution, e.g., 1,4-dioxane. The reaction flask is then purged with nitrogen, a palladium catalyst (0.01-0.2 equivalents or about 0.05 equivalents) such as methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) is added, the reaction mixture is stirred and heated at 80-130°C or about 110°C until the reaction is complete, or for 2-24 hours or for 8-24 hours. The reaction mixture is then worked up, for example by partitioning between dichloromethane and saturated sodium bicarbonate solution, and the solvent layer (e.g. dichloromethane) is collected, dried (e.g. by using sodium sulfate), and then concentrated (e.g. by rotary evaporation). The resulting crude product is then purified, for example by silica gel chromatography (0-10% methanol / dichloromethane gradient). Deprotection [ka]

[0055] Method A The product of the Suzuki reaction above can be dissolved in a volume of a solvent such as methanol sufficient to provide a solution concentration of 0.05-1 mmol or 0.1-0.2 mmol, then concentrated HCl equal to about 1 / 2 the volume of the solvent (e.g., methanol) used is added, and the reaction mixture is stirred and heated at 35-65°C or about 50°C until completion, or for 1-24 h or 4-24 h. Standard isolation techniques can be used to obtain the product, including those described below. For small-scale reactions (solution volume <5 mL), the reaction mixture is then partially concentrated to remove most of the solvent (e.g., methanol), and the resulting solution is diluted with a solvent / water mixture, e.g., acetonitrile / water mixture, and purified, e.g., by reverse phase chromatography (e.g., 5-70% acetonitrile / water gradient with 0.05% TFA). For larger scale reactions, the reaction mixture is added dropwise to aqueous ammonia (e.g., concentrated ammonia solution diluted 1:5 in water) to precipitate the product, which is then collected by filtration. The resulting solid is then purified by reverse phase chromatography (5-70% acetonitrile / water gradient with 0.05% TFA).

[0056] Method B The product of the Suzuki reaction can be dissolved in a mixture of 4M HCl in 1,4-dioxane (30-40 equivalents) and water (approximately 5-50% or 20% of the volume of the HCl / dioxane solution), and the reaction mixture is then stirred and heated at 40-80° C. or 60° C. until completion, or for 1-48 h or 8-48 h. The reaction mixture is then frozen and lyophilized, and the resulting solid is purified, for example, by reverse phase chromatography (e.g., a gradient of 0-70% acetonitrile / water with 0.05% TFA).

[0057] Method C The product of the Suzuki reaction is dissolved in TFA (30-50 equiv.) and the reaction mixture is stirred at room temperature until completion or for 1-24 h. The reaction mixture is then concentrated by rotary evaporation and the crude product is purified, for example, by preparative HPLC (e.g., a gradient of 5-70% acetontrile / water with 0.05% TFA).

[0058] The A ring may be further substituted using conventional chemistry as illustrated in the Examples section.

[0059] Pharmaceutical Compositions The compounds of the present invention and the present disclosure and their pharmaceutically acceptable salts can typically be used in the form of pharmaceutical compositions or preparations.Such pharmaceutical compositions can be advantageously administered to patients by inhalation.In addition, pharmaceutical compositions can be administered by any acceptable administration route, including but not limited to oral, rectal, nasal, topical (including transdermal) and parenteral administration modes.

[0060] Thus, in one of its composition aspects, the present invention is directed to a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or excipient and a compound of formula (I) or formula (II), where "a compound of formula (I)" means a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and "a compound of formula (II)" means a compound of formula (II) or a pharma- ceutically acceptable salt thereof, as defined above. Optionally, such pharmaceutical compositions may contain other therapeutic agents and / or formulating agents, if desired. In some embodiments, such pharmaceutical compositions further comprise one or more other therapeutic agents. In some embodiments, the one or more other therapeutic agents are useful for treating a respiratory disease in a mammal (e.g., a human).

[0061] When discussing compositions and their uses, the "compounds of the invention" or "compounds of the disclosure" may also be referred to herein as "active agents." As used herein, the term "compounds of the invention" or "compounds of the disclosure" includes all compounds encompassed by and embodied in Formula (I) or Formula (II), as well as pharmaceutically acceptable salts thereof.

[0062] The pharmaceutical compositions of the present disclosure typically contain a therapeutically effective amount of the compounds of the present disclosure. However, those skilled in the art will recognize that the pharmaceutical compositions may contain amounts that are greater than the therapeutically effective amount, i.e., bulk compositions, or amounts that are less than the therapeutically effective amount, i.e., individual unit doses designed for multiple administration to achieve a therapeutically effective amount.

[0063] Typically, such pharmaceutical compositions contain from about 0.01 to about 95% by weight of active agent (including, for example, from about 0.05 to about 30% by weight) and from about 0.1% to about 10% by weight of active agent. In some embodiments, the pharmaceutical composition contains from 0.1 mg to 100 mg of active agent, including, for example, from 1 mg to 10 mg of active agent, including, for example, from 1 mg to 20 mg of active agent.

[0064] Any conventional carrier or excipient may be used in the pharmaceutical composition of the present disclosure. The selection of a particular carrier or excipient, or combination of carriers or excipients, depends on the mode of administration used to treat a particular patient, or the type of medical condition or disease state. In this respect, the preparation of a pharmaceutical composition suitable for a particular mode of administration is well within the skill of the person skilled in the art of pharmacy. In addition, the carrier or excipient used in the pharmaceutical composition of the present disclosure is commercially available. As further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Maryland (2000); and HC Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Maryland (1999).

[0065] Representative examples of materials which may function as pharma- ceutically acceptable carriers include, but are not limited to, sugars (e.g., lactose, glucose, and sucrose); starches (e.g., corn starch and potato starch); cellulose (e.g., microcrystalline cellulose) and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate); powdered tragacanth; malt; gelatin; talc; excipients (e.g., cocoa butter and suppository wax); oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); glycols (e.g., propylene glycol); polyols (e.g., glycerin, sorbitol, mannitol, and polyethylene glycol); esters (e.g., ethyl oleate and ethyl laurate); agar; buffers (e.g., magnesium hydroxide and aluminum hydroxide); alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical compositions.

[0066] Pharmaceutical compositions are typically prepared by thoroughly and thoroughly mixing or blending the active agent with a pharma- ceutically acceptable carrier and one or more optional ingredients. The resulting homogeneously blended mixture can then be shaped or filled into tablets, capsules, pills, and the like, using conventional procedures and equipment.

[0067] In some embodiments, pharmaceutical composition is suitable for inhalation administration.The pharmaceutical composition for inhalation administration is typically in the form of aerosol or powder.Such composition is generally administered by using inhalation delivery device, such as dry powder inhaler (DPI), metered dose inhaler (MDI), nebulizer inhaler or similar delivery device.

[0068] In certain embodiments, the pharmaceutical composition is administered by inhalation using a dry powder inhaler. Such dry powder inhalers typically administer the pharmaceutical composition as a free-flowing powder that is dispersed in the patient's airstream during inspiration. To achieve a free-flowing powder composition, the therapeutic agent is typically formulated with suitable excipients such as lactose, starch, mannitol, dextrose, polylactic acid (PLA), polylactide-co-glycolide (PLGA) or combinations thereof. Typically, the therapeutic agent is micronized and combined with a suitable carrier to form a composition suitable for inhalation.

[0069] The representative pharmaceutical composition for use in dry powder inhaler comprises lactose and the compound of the present disclosure in micronized form.Such dry powder composition can be made by, for example, combining dry-milled lactose with therapeutic agent, and then dry-mixing the components.The composition is then typically loaded into dry powder dispenser or into inhalation cartridge or capsule for use with dry powder delivery device.

[0070] Suitable dry powder inhaler delivery devices for administering therapeutic agents by inhalation have been described in the art, and examples of such devices are commercially available.For example, representative dry powder inhaler delivery devices or products include Aeolizer (Novartis); Airmax (IVAX); ClickHaler (Innovata Biomed); Diskhaler (GlaxoSmithKline); Diskus / Accuhaler (GlaxoSmithKline); Ellipta (GlaxoSmithKline); Easyhaler (Orion Pharma); Eclipse (Aventis); FlowCaps (Hovione); Handihaler (Boehringer Ingelheim); Pulvinal (Chiesi); Rotahaler (GlaxoSmithKline); SkyeHaler / Certihaler (SkyePharma); Twisthaler (Schering-Plough); Turbuhaler (AstraZeneca); Ultrahaler (Aventis), etc.

[0071] In another specific embodiment, the pharmaceutical composition is administered by inhalation using a metered dose inhaler. Such metered dose inhalers typically release a measured amount of therapeutic agent using compressed propellant gas. Thus, the pharmaceutical composition administered using a metered dose inhaler typically comprises a solution or suspension of therapeutic agent in a liquefied propellant. Any suitable liquefied propellant can be used, including hydrofluoroalkanes (HFAs) such as 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoro-n-propane, (HFA227), and chlorofluorocarbons such as CCl3F. In certain embodiments, the propellant is a hydrofluoroalkane. In some embodiments, the hydrofluoroalkane formulation contains a cosolvent such as ethanol or pentane, and / or a surfactant such as sorbitan trioleate, oleic acid, lecithin, and glycerin.

[0072] A typical pharmaceutical composition for use in a metered dose inhaler comprises about 0.01% to about 5% by weight of a compound of the present disclosure; about 0% to about 20% by weight of ethanol; about 0% to about 5% by weight of a surfactant; and the remainder is HFA propellant. Such compositions are typically prepared by adding chilled or pressurized hydrofluoroalkane to a suitable container containing the therapeutic agent, ethanol (if present) and surfactant (if present). To prepare a suspension, the therapeutic agent is micronized and then combined with the propellant. The composition is then loaded into an aerosol canister that typically forms part of a metered dose inhaler device.

[0073] Metered dose inhaler devices suitable for administering therapeutic agents by inhalation have been described in the art, and examples of such devices are commercially available. For example, representative metered dose inhaler devices or products include AeroBid Inhaler System (Forest Pharmaceuticals); Atrovent Inhalation Aerosol (Boehringer Ingelheim); Flovent (GlaxoSmithKline); Maxair Inhaler (3M); Proventil Inhaler (Schering); Serevent Inhalation Aerosol (GlaxoSmithKline), etc.

[0074] In some embodiments, pharmaceutical compositions are administered by inhalation using a nebulizer inhaler. Such nebulizer devices typically generate a high-velocity air stream that causes pharmaceutical compositions to atomize as mist that is carried into the patient's respiratory tract. Thus, when formulated for use in a nebulizer inhaler, therapeutic agents can be dissolved in a suitable carrier to form a solution. Alternatively, therapeutic agents can be micronized or nano-milled and combined with a suitable carrier to form a suspension.

[0075] Representative pharmaceutical compositions for use in nebulizer inhalers include solutions or suspensions containing about 0.05 μg / mL to about 20 mg / mL of a compound of the present disclosure and excipients compatible with nebulized formulations. In one embodiment, the solution has a pH of about 3 to about 8.

[0076] Nebulizer devices suitable for administering therapeutic agents by inhalation are described in the art, and examples of such devices are commercially available.For example, representative nebulizer devices or products include Respimat Softmist inhaler (Boehringer Ingelheim); AERx Pulmonary Delivery System (Aradigm Corp.); PARI LC Plus Reusable Nebulizer (Pari GmbH), etc.

[0077] In yet another embodiment, the pharmaceutical composition of the present disclosure can be prepared in the form of dosage form intended for oral administration.The pharmaceutical composition suitable for oral administration can be in the form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules;or as a solution or suspension in aqueous or non-aqueous liquid;or as an oil-in-water or water-in-oil liquid emulsion;or as an elixir or syrup, etc.;each containing a predetermined amount of the compound of the present disclosure as active ingredient.

[0078] When intended for oral administration in solid dosage form, the pharmaceutical composition of the present disclosure typically comprises an active agent and one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate.Optionally or alternatively, such solid dosage forms may also comprise fillers or extenders, binders, wetting agents, dissolution retarders, absorption promoters, wetting agents, absorbing agents, lubricants, coloring agents, and buffers.Releasing agents, wetting agents, coating agents, sweeteners, flavorings and perfumes, preservatives, and antioxidants may also be present in the pharmaceutical composition of the present disclosure.

[0079] Alternative formulations may also include controlled release formulations, liquid dosage forms for oral administration, transdermal patches, and parenteral formulations. Conventional excipients and methods of preparation of such alternative formulations are described, for example, in the references by Remington, supra.

[0080] The following non-limiting examples illustrate representative pharmaceutical compositions of the present disclosure.

[0081] dry powder composition Micronized compound of formula (I) or formula (II) (1 g) is mixed with milled lactose (25 g). This mixed mixture is then loaded into individual blisters of a peelable blister pack in an amount sufficient to provide about 0.1 mg to about 4 mg of compound of formula (I) or formula (II) per dose. The contents of the blister are administered using a dry powder inhaler.

[0082] dry powder composition Micronized compound of Formula (I) or Formula (II) (1 g) is mixed with milled lactose (20 g) to form a bulk composition having a weight ratio of compound to milled lactose of 1:20. The mixed composition is loaded into a dry powder inhalation device capable of delivering about 0.1 mg to about 4 mg of compound of Formula (I) or Formula (II) per dose.

[0083] Metered dose inhaler composition Micronized compound of formula (I) or formula (II) (10 g) is dispersed in a solution prepared by dissolving lecithin (0.2 g) in demineralized water (200 mL). The resulting suspension is spray dried and then micronized to form a micronized composition comprising particles having an average diameter of less than about 1.5 μm. The micronized composition is then loaded into a metered dose inhaler cartridge containing pressurized 1,1,1,2-tetrafluoroethane in an amount sufficient to provide about 0.1 mg to about 4 mg of compound (I) or formula (II) per dose when administered by a metered dose inhaler.

[0084] Nebulizer Composition Dissolve a compound of Formula (I) or Formula (II) (25 mg) in a solution containing 1.5 to 2.5 equivalents of hydrochloric acid, then add sodium hydroxide to adjust the pH to 3.5 to 5.5, and add 3% by weight of glycerol. Stir the solution thoroughly until all ingredients are dissolved. Administer the solution using a nebulizer device that provides about 0.1 mg to about 4 mg of the compound of Formula (I) or Formula (II) per dose.

[0085] usefulness The compounds of the present disclosure are Janus kinase (JAK) inhibitors.The JAK inhibitors of the present disclosure have been designed for the treatment of inflammatory and fibrotic diseases, including inflammatory and fibrotic diseases of the airway.In particular, the compounds have been designed to allow the direct delivery of potent anti-cytokine agents to the site of action of respiratory diseases in the lungs, while limiting systemic exposure.

[0086] As shown in Assays 1-2 and Table 1, compounds of the present disclosure were shown to be potent inhibitors of the JAK family of enzymes: JAK1, JAK2, JAK3, and TYK2.

[0087] It is recognized that the broad anti-inflammatory effects of JAK inhibitors may suppress normal immune cell function, potentially increasing the risk of infection. Therefore, the compounds are optimized to limit absorption from the lungs to plasma, thus minimizing the risk of immunosuppression. As described in the experimental section below, the absorption and distribution of select compounds were profiled in preclinical assays. In mice, several compounds were tested in assay 4 and showed high concentrations after administration in lung tissue and low absorption to plasma.

[0088] Compounds 1-3 were shown to inhibit the effects of the pro-inflammatory cytokine IL-13 in mouse lung tissue. Specifically, the compounds showed inhibition of IL-13-induced phosphorylation of STAT6 in lung tissue, providing evidence of local pulmonary JAK target binding in vivo. This effect was observed when the pro-inflammatory cytokine IL-13 was administered 8 hours after administration of the test compounds, providing further evidence of significant retention in the lung.

[0089] Anti-inflammatory activity of JAK inhibitors has been robustly demonstrated in preclinical models of asthma (Malaviya et al., Int. Immunopharmacol., 2010, 10, 829-836; Matsunaga et al., Biochem. and Biophys. Res. Commun., 2011, 404, 261-267; Kudlacz et al., Eur. J. Pharmacol, 2008, 582, 154-161). Cytokines involved in asthmatic inflammation that signal through the JAK-STAT pathway include IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon-γ (IFNγ), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Therefore, the compounds of the present disclosure are expected to be useful in treating inflammatory respiratory disorders, particularly asthma.Inflammation and fibrosis of the lungs are characteristic of other respiratory diseases in addition to asthma, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pneumonitis, interstitial lung disease (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans and sarcoidosis.Therefore, the compounds are expected to be useful in treating chronic obstructive pulmonary disease, cystic fibrosis, pneumonitis, interstitial lung disease (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans and sarcoidosis. Furthermore, asthma endotypes can be broadly recognized as type 2 (T2)-high or T2-low (Kuruvilla et al, Clin Rev Allergy Immunol, 2019, 56(2), 219-233). Based on their mechanism of action, the compounds of the present disclosure have the potential to treat both T2-high and T2-low endotypes.

[0090] The compounds of the present disclosure have biological activity involving the inhibition of cytokines associated with inflammation, and are therefore expected to be useful in the treatment of certain specific respiratory diseases, as detailed below.

[0091] Eosinophilic airway inflammation is a characteristic feature of diseases collectively termed eosinophilic lung diseases (Cottin et al., Clin. Chest. Med., 2016, 37(3), 535-56). Eosinophilic diseases have been associated with IL-4, IL-13 and IL-5 signaling. Eosinophilic lung diseases include infections (especially helminth infections), drug-induced pneumonitis (e.g., induced by therapeutic agents such as antibiotics, phenytoin or l-tryptophan), fungal-induced pneumonitis (e.g., allergic bronchopulmonary aspergillosis), hypersensitivity pneumonitis and eosinophilic polyangiitis granulomatosis (previously known as Churg-Strauss syndrome). Eosinophilic lung diseases of unknown etiology include idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome and Löffler syndrome.

[0092] Polymorphisms in the IL-6 gene are associated with elevated IL-6 levels and increased risk of developing pulmonary arterial hypertension (PAH) (Fang et al., J. Am. Soc. Hypertens., 2017, 11(3), 171-177). Reinforcing the role of IL-6 in PAH, inhibition of the IL-6 receptor chain gp130 ameliorated disease in a rat model of PAH (Huang et al., Can. J. Cardiol., 2016, 32(11), 1356.e1-1356.e10).

[0093] Cytokines such as IFNγ, IL-12 and IL-6 have been implicated in various non-allergic lung diseases such as sarcoidosis and lymphangioleiomyomatosis (El-Hashemite et al., Am. J. Respir. Cell. Mol. Biol., 2005, 33, 227-230 and El-Hashemite et al., Cancer Res., 2004, 64, 3436-3443).

[0094] Bronchiectasis and infiltrative lung diseases are diseases associated with chronic neutrophilic inflammation.

[0095] Pathological T cell activation is important in the pathogenesis of multiple respiratory diseases. Autoreactive T cells play a role in bronchiolitis obliterans organizing pneumonia (also called COS). Similar to COS, the pathogenesis of lung transplant rejection is associated with abnormal T cell activation of recipient T cells by transplanted donor lungs. Lung transplant rejection can occur early as primary graft dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR) or lymphocytic bronchiolitis (LB), or it can occur several years after lung transplantation as chronic transplant pulmonary dysfunction (CLAD). CLAD was previously known as bronchiolitis obliterans (BO) but is now considered a syndrome that may have different pathological manifestations including BO, restrictive CLAD (rCLAD or RAS) and neutrophilic allograft dysfunction. Chronic transplant pulmonary dysfunction (CLAD) is a major challenge in the long-term management of lung transplant recipients, as it gradually causes the transplanted lung to lose functionality (Gauthier et al., Curr Transplant Rep., 2016, 3(3), 185-191). CLAD is poorly responsive to treatment, and therefore there is still a need for effective compounds that can prevent or treat this condition. Several JAK-dependent cytokines, such as IFNγ and IL-5, are upregulated in CLAD and lung transplant rejection (Berastegui et al., Clin. Transplant. 2017, 31, e12898). Furthermore, high pulmonary levels of CXCR3 chemokines, such as CXCL9 and CXCL10, downstream of JAK-dependent IFN signaling, are associated with worse outcomes in lung transplant patients (Shino et al., PLOS One, 2017, 12(7), e0180281). Systemic JAK inhibition has been shown to be effective in renal transplant rejection (Vicenti et al., American Journal of Transplantation, 2012, 12, 2446-56).Therefore, JAK inhibitors have the potential to be effective in treating or preventing lung transplant rejection and CLAD.Similar T cell activation events described as the basis of lung transplant rejection are also believed to be the main driver of pulmonary graft-versus-host disease (GVHD) that can occur after hematopoietic stem cell transplantation.Like CLAD, pulmonary GVHD is a chronic progressive condition with extremely poor outcomes, and currently no treatment is approved. A retrospective multicenter survey study of 95 patients with steroid-resistant acute or chronic GVHD who received the systemic JAK inhibitor ruxolitinib as salvage therapy demonstrated complete or partial response to ruxolitinib in the majority of patients, including those with pulmonary GVHD (Zeiser et al., Leukemia, 2015, 29, 10, 2062-68). Because systemic JAK inhibition is associated with serious adverse events and a small therapeutic index, there remains a need for inhaled lung-directed non-systemic JAK inhibitors to prevent or delay lung transplant rejection or pulmonary GVHD. The compounds of the present disclosure have the characteristics required to meet this need.

[0096] Thus, provided herein is a method of treating or preventing lung transplant rejection in a human in need thereof, comprising administering to the human a compound of Formula (I) or Formula (II) or a pharma- ceutically acceptable salt thereof. In some embodiments, the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic transplant pulmonary dysfunction. In some embodiments, the lung transplant rejection is acute lung transplant rejection. In some embodiments, the lung transplant rejection is chronic transplant pulmonary dysfunction. In some embodiments, the lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic transplant pulmonary dysfunction, and neutrophilic allograft dysfunction.

[0097] More recently, immune checkpoint inhibitors have induced pneumonitis, another T cell-mediated lung disease that has emerged with the increasing use of immune checkpoint inhibitors.Cancer patients treated with these T cell stimulants may develop fatal pneumonitis.The compounds of the present disclosure have biological activity that allows them to inhibit IFNγ secretion.

[0098] In one embodiment, therefore, the present disclosure provides a method of treating a respiratory disease in a mammal (e.g., a human), comprising the step of administering to the mammal (or human) a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof.

[0099] In some embodiments, the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonitis, cystic fibrosis (CF), pneumonitis, interstitial lung disease (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, or sarcoidosis. In some embodiments, the respiratory disease is asthma or chronic obstructive pulmonary disease. In some embodiments, the asthma is T2-high asthma. In some embodiments, the asthma is T2-low asthma.

[0100] In some embodiments, the respiratory disease is a pulmonary infection, an eosinophilic disease, a helminth infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonitis, fungal-induced pneumonitis, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic polyangiitis granulomatosis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler's syndrome, bronchiolitis obliterans organizing pneumonia, acute and chronic lung transplant rejection (including PGD, OP, LB, AR and CLAD, BO, restrictive CLAD and neutrophilic allograft dysfunction), pulmonary graft versus host disease, or immune checkpoint inhibitor-induced pneumonitis.

[0101] The present disclosure further provides a method of treating asthma in a mammal (e.g., a human), comprising the step of administering to the mammal (or human) a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof.

[0102] When used to treat asthma, the compound of the present disclosure is typically administered in a single dose or multiple doses per day, although other administration forms can be used.The amount of active agent administered per dose or the total amount administered per day will usually be determined by a physician in light of the relevant circumstances, including the symptoms to be treated, the route of administration selected, the actual compound administered and its relative activity, the age, weight and response of individual patient, the severity of the patient's symptoms, etc.

[0103] The present disclosure further provides a method of treating a respiratory disease (including but not limited to those diseases described herein) in a mammal (e.g., a human), comprising the step of administering to the mammal (or human) a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof.

[0104] When used to treat respiratory diseases (including but not limited to those described herein), the compounds of the present disclosure are typically administered in a single dose or multiple doses per day, although other administration forms may be used.The amount of active agent administered per dose or the total amount administered per day will usually be determined by a physician in light of the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0105] Human coronaviruses are common respiratory pathogens that typically induce mild upper respiratory tract disease. Two highly pathogenic viruses, severe acute respiratory syndrome-related coronavirus (SARS-CoV-1) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), have caused severe respiratory syndromes resulting in mortality rates of over 10% and over 35%, respectively (Assiri et al., N Engl J Med., 2013, 369, 407-1). The recent emergence of coronavirus disease 2019 (COVID-19 and the ensuing pandemic) has created a global medical emergency. Similar to SARS-CoV-1 and MERS-CoV, a proportion of patients (~16%) may develop severe respiratory illness manifested by acute lung injury (ALI), leading to ICU admission (~5%), respiratory failure (~6.1%) and death (Wang et al., JAMA, 2020, 323, 11, 1061-1069; Guan et al., N Engl J Med., 2020, 382, ​​1708-1720; Huang et al., The Lancet, 2020.395(10223), 497-506; Chen et al., The Lancet, 2020, 395(10223), 507-13). A subgroup of COVID-19 patients appears to have a hyperinflammatory “cytokine storm” leading to acute lung injury and acute respiratory distress syndrome (ARDS). This cytokine storm can also spread to the systemic circulation, resulting in sepsis and ultimately multiple organ dysfunction syndrome. The dysregulated cytokine signaling seen in COVID-19 is characterized by increased expression of interferons (IFNs), interleukins (ILs) and chemokines, leading to ALI and associated mortality. This hyperinflammatory response can potentially be modulated and treated by lung-selective pan-Janus kinase (JAK) inhibitors.A monoclonal antibody directed against IL-6 (tocilizumab) appears to be effective in treating patients with ALI from COVID-19 (Xu X, Han M, Li T, Sun W, Wang D, Fu B et al., Effective Treatment of Severe COVID-19 Patients with Tocilizumab, 2020, PNAS, https: / / doi.org / 10.1073 / pnas.2005615117). Infection with mouse-adapted strains of the 2003 SARS-CoV-1 and 2012 MERS-CoV, as well as transgenic mice expressing the human SARS-CoV-1 receptor hACE2 infected with human SARS-CoV-1, demonstrate elevated JAK-dependent cytokines such as IFNγ, IL-6 and IL-12, as well as downstream chemokines such as chemokine (C-C motif) ligand 10 (CCL10), CCL2 and CCL7 (McCray et al., J Virol., 2007, 81(2), 813-21; Gretebeck et al., Curr Opin Virol. 2015, 13, 123-9, Day et al., Virology. 2009, 395(2), 210-22. JAK inhibitors have also been shown to be beneficial in mouse models of ALI induced by lipopolysaccharide or ganciclovir (Severgnini et al., Am J Respir Crit Care Med., 2005, 171(8), 858-67; Jin et al., Am J Physiol-Lung Cell Mol Physiol., 2018, 314(5), L882-92).Finally, based on the results of clinical trials, baricitinib, a JAK inhibitor, received emergency use authorization (EUA) in combination with remdesivir for the treatment of COVID-19 in patients requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (https: / / www.fda.gov / news-events / press-announcements / coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19#:~:text=Today%2C%20the%20U.S.%20Food%20and,or%20older%20requiring%20supplemental%20oxygen%2C). In clinical trials of hospitalized COVID-19 patients, baricitinib in combination with remdesivir was shown to reduce time to recovery within 29 days of starting treatment compared to patients who received a placebo along with remdesivir.

[0106] Thus, the compounds of formula (I) or formula (II), which are lung-selective inhaled pan-JAK inhibitors, may be uniquely suited to attenuate the cytokine storm associated with COVID-19. By delivering to the lungs and avoiding systemic immunosuppression, additional infections that lead to worsening mortality may also be avoided. This is especially true for patients who require ventilatory support. As the main cause of death in subjects with COVID-19 appears to be comorbidities and superinfections, inhaled drugs may be a way to avoid systemic immunosuppression that predisposes patients to these risks.

[0107] Thus, the present disclosure provides a method of treating a mammal (or patient) infected with a coronavirus, such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV, or a symptom thereof, comprising administering to the mammal (or patient) a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of the present disclosure or a pharma- ceutically acceptable salt thereof. The present disclosure also provides a method of treating ALI and / or ARDS in a mammal (or patient) caused by a coronavirus infection (such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV), comprising administering to the mammal (or patient) a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of the present disclosure or a pharma- ceutically acceptable salt thereof.

[0108] The mechanism of action of JAK inhibitors is relevant for the treatment of rhinitis diseases (Therapeutic Effects of Intranasal Tofacitinib on Chronic Rhinosinusitis with Nasal Polyps in Mice, Joo et al., The Laryngoscope, 2020, https: / / doi.org / 10.1002 / lary.29129). In addition, dupilumab, which acts by blocking the IL-4 and IL-13 signaling pathways, has been approved for the treatment of chronic rhinosinusitis with nasal polyps.

[0109] Thus, also provided herein is a method of treating a rhinitis disease in a mammal (e.g., a human), comprising administering to the mammal (or human) a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of the present disclosure or a pharma- ceutically acceptable salt thereof. In some embodiments, the rhinitis disease is selected from the group consisting of chronic rhinosinusitis with or without nasal polyps, nasal polyposis, sinusitis with nasal polyps, and rhinitis (non-allergic, allergic, perennial, and vasomotor rhinitis).

[0110] As JAK inhibitors, the compounds of the present disclosure can also be useful for various other diseases.The compounds of the present disclosure can be useful for various gastrointestinal inflammatory indications, including but not limited to inflammatory bowel disease, ulcerative colitis (proctosigmoiditis, pancolitis, ulcerative proctitis and left-sided colitis), Crohn's disease, collagenous colitis, lymphocytic colitis, Behcet's disease, celiac disease, immune checkpoint inhibitor-induced colitis, ileitis, eosinophilic esophagitis, graft-versus-host disease-associated colitis and infectious colitis. Ulcerative colitis (Reimund et al., J. Clin. Immunology, 1996, 16, 144-150), Crohn's disease (Woywodt et al., Eur. J. Gastroenterology Hepatology, 1999, 11, 267-276), collagenous colitis (Kumawat et al., Mol. Immunology, 2013, 55, 355-364), lymphocytic colitis (Kumawat et al., 2013), eosinophilic esophagitis (Weinbrand-Goichberg et al., Immunol. Res., 2013, 56, 249-260), graft-versus-host disease-associated colitis (Coghill et al., Blood, 2001, 117, 3268-3276), infectious colitis (Stallmach et al., Int. J. Colorectal Dis., 2004, 19, 308-315), Behcet's disease (Zhou et al., Autoimmun. Rev., 2012, 11, 699-704), celiac disease (de Nitto et al., World J. Gastroenterol., 2009, 15, 4609-4614), immune checkpoint inhibitor-induced colitis (e.g., CTLA-4 inhibitor-induced colitis; (Yano et al., J. Translation. Med., 2014, 12, 191), PD-1 or PD-L1 inhibitor-induced colitis) and ileitis (Yamamoto et al., Dig. Liver Dis., 2008, 40, 253-259) are characterized by elevated levels of certain pro-inflammatory cytokines. Since many pro-inflammatory cytokines signal through JAK activation, the compounds described in this application may be able to reduce inflammation and provide symptomatic relief.In particular, the compounds of the present disclosure may be useful for inducing and maintaining remission of ulcerative colitis, and treating gastrointestinal adverse effects in Crohn's disease, immune checkpoint inhibitor-induced colitis, and graft-versus-host disease.Thus, in one embodiment, the present disclosure provides a method for treating gastrointestinal inflammatory disease in a mammal (e.g., a human), comprising administering to the mammal a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and the compound or a pharma- ceutically acceptable salt thereof.

[0111] Atopic dermatitis and other inflammatory skin diseases have been associated with an elevation of pro-inflammatory cytokines that are dependent on the JAK-STAT pathway. Thus, the compounds of the present disclosure or pharmacologic acceptable salts thereof may be used to treat atopic dermatitis, alopecia areata, vitiligo, psoriasis, dermatomyositis, cutaneous T-cell lymphoma (Netchiporouk et al., Cell Cycle 2014;13,3331-3335) and subtypes (Sézary syndrome, mycosis fungoides, pagetoid reticulosis, granulomatous loose skin, lymphomatoid papulosis, chronic pityriasis lichenoides, acute pityriasis lichenoides, CD30+ cutaneous T-cell lymphoma, secondary cutaneous CD30-positive large cell lymphoma, non-mycosis fungoides CD30-negative cutaneous large T-cell lymphoma, pleomorphic T-cell lymphoma, Lennart's lymphoma, cutaneous T-cell ... In some cases, the treatment may be beneficial in a number of skin inflammatory or pruritic conditions, including, but not limited to, cutaneous leukemia, subcutaneous T-cell lymphoma, angiocentric lymphoma, blastic NK-cell lymphoma), prurigo nodularis, lichen planus, primary localized cutaneous amyloidosis, bullous pemphigoid, cutaneous manifestations of graft-versus-host disease, pemphigoid, discoid lupus, granuloma annulare, lichen simplex chronicus, vulvar / scrotal / perianal pruritus, lichen sclerosus, postherpetic neuralgia itch, lichen planus pilaris, and foliculitis decalvans.In particular, atopic dermatitis (Bao et al., JAK-STAT, 2013, 2, e24137), alopecia areata (Xing et al., Nat. Med. 2014, 20, 1043-1049), vitiligo (Craiglow et al., JAMA Dermatol. 2015, 151, 1110-1112), prurigo nodularis (Sonkoly et al., J. Allergy Clin. Immunol. 2006, 117, 411-417), lichen planus (Welz-Kubiak et al., J. Immunol. Res. 2015, ID: 854747), primary localized cutaneous amyloidosis (Tanaka et al., Br. J. Dermatol. 2009, 161, 1217-1224), bullous pemphigoid (Feliciani et al., Int. J. Immunopathol. Pharmacol. 1999, 12, 55-61) and cutaneous manifestations of graft-versus-host disease (Okiyama et al., J. Invest. Dermatol. 2014, 134, 992-1000) are characterized by the elevation of certain cytokines that signal through the activation of JAK. Thus, the compounds of the present disclosure or pharma- ceutically acceptable salts thereof may be capable of alleviating the associated skin inflammation or pruritus caused by these cytokines. In particular, the compound of the present disclosure or its pharmaceutically acceptable salt can be expected to be useful in the treatment of atopic dermatitis and other inflammatory skin diseases.Thus, in one embodiment, the present disclosure provides a method for treating inflammatory skin diseases in mammals (e.g., humans), comprising applying a pharmaceutical composition comprising the compound of the present disclosure or its pharmaceutically acceptable salt and pharmaceutical carrier to the skin of the mammal.In some embodiments, the inflammatory skin disease is atopic dermatitis.

[0112] It has been shown that many eye diseases are related to the elevation of proinflammatory cytokines that depend on JAK-STAT pathway.Therefore, the compound of the present disclosure or its pharmacologic acceptable salt can be useful for treating some eye diseases, including but not limited to uveitis, diabetic retinopathy, diabetic macular edema, dry eye, age-related macular degeneration and atopic keratoconjunctivitis. In particular, uveitis (Horai and Caspi, J. Interferon. Cytokine Res., 2011, 31, 733-744), diabetic retinopathy (Abcouwer, J. Clin. Cell. Immunol., 2013, Suppl 1, 1-12), diabetic macular edema (Sohn et al., American Journal of Opthamology, 2011, 152, 686-694), dry eye (Stevenson et al., Arch. Ophthalmol., 2012, 130, 90-100), and age-related macular degeneration (Knickelbein et al., Int. Ophthalmol. Clin., 2015, 55(3), 63-78) are characterized by the elevation of certain pro-inflammatory cytokines that signal through the JAK-STAT pathway. Thus, the compound of the present disclosure or its pharmaceutically acceptable salt may be able to alleviate the associated ocular inflammation and reverse the progression of the disease or provide symptomatic relief. Thus, in one embodiment, the present disclosure provides a method of treating an ocular disease in a mammal (e.g., a human), comprising administering to the eye of the mammal (or human) a pharmaceutical composition comprising a compound of the present disclosure or its pharmaceutically acceptable salt and a pharmaceutical carrier. In some embodiments, the ocular disease is uveitis, diabetic retinopathy, diabetic macular edema, dry eye, age-related macular degeneration, or atopic keratoconjunctivitis. In some embodiments, the method comprises administering the compound of the present disclosure or its pharmaceutically acceptable salt by intravitreal injection. The compound of the present disclosure or its pharmaceutically acceptable salt may also be used in combination with one or more compounds useful for ocular disease.

[0113] The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, may also be useful in treating other diseases, such as other inflammatory diseases, autoimmune diseases, or cancer. The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, may be useful in treating one or more of cytokine release syndrome (CRS), arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, graft rejection, xerophthalmia, psoriatic arthritis, diabetes, insulin-dependent diabetes mellitus, motor neuron disease, myelodysplastic syndrome, pain, sarcopenia, cachexia, septic shock, systemic lupus erythematosus, leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, ankylosing spondylitis, myelofibrosis, B-cell lymphoma, hepatocellular carcinoma, Hodgkin's disease, breast cancer, multiple myeloma, melanoma, non-Hodgkin's lymphoma, non-small cell lung cancer, ovarian clear cell carcinoma, ovarian tumor, pancreatic tumor, polycythemia vera, Sjogren's syndrome, soft tissue sarcoma, sarcoma, splenomegaly, T-cell lymphoma, and thalassemia major.

[0114] Combination therapy The compounds of the present disclosure or their pharma- ceutically acceptable salts can be used in combination with one or more agents that act by the same mechanism or by different mechanisms to treat diseases. Different agents can be administered sequentially or simultaneously in separate compositions or the same composition. Useful classes of agents for combination therapy include β2 adrenergic receptor agonists, muscarinic receptor antagonists, glucocorticoid agonists, G protein-coupled receptor 44 antagonists, leukotriene D4 antagonists, muscarinic M3 receptor antagonists, histamine H1 receptor antagonists, immunoglobulin E antagonists, PDE4 inhibitors, IL-4 antagonists, muscarinic M1 receptor antagonists, histamine receptor antagonists, IL- 13 antagonists, IL-5 antagonists, 5-lipoxygenase inhibitors, beta-adrenergic receptor agonists, CCR3 chemokine antagonists, CFTR stimulators, immunoglobulin modulators, interleukin-33 ligand inhibitors, PDE3 inhibitors, phosphoinositide-3 kinase delta inhibitors, thromboxane A2 antagonists, elastase inhibitors, Kit tyrosine kinase inhibitors, leukotriene E4 antagonists, leukotriene antagonists, PGD 2 antagonists, TNFα ligand inhibitors, TNF binders, complement cascade inhibitors, eotaxin ligand inhibitors, glutathione reductase inhibitors, histamine H4 receptor antagonists, IL-6 antagonists, IL2 gene stimulators, immunoglobulin gamma Fc receptor IIB modulators, interferon gamma ligands, interleukin 13 ligand inhibitors, interleukin 17 ligand inhibitors, L-selectin antagonists, leukocyte elastase inhibitors, leukotriene ... triene C4 antagonists, leukotriene C4 synthase inhibitors, membrane copper amine oxidase inhibitors, metalloprotease-12 inhibitors, metalloprotease-9 inhibitors, mite allergen modulators, muscarinic receptor modulators, nicotinic acetylcholine receptor agonists, nuclear factor kappa B inhibitors, p-selectin antagonists, PDE5 inhibitors, PDGF receptor antagonists, phosphoinositide-3 kinase gamma agonists, TLR-7 agonists, TNF antagonists,Abl tyrosine kinase inhibitors, acetylcholine receptor antagonists, acidic mammalian chitinase inhibitors, ACTH receptor agonists, actin polymerization regulators, adenosine A1 receptor antagonists, adenylate cyclase stimulators, adrenergic receptor antagonists, adrenocorticotropic hormone ligands, alcohol dehydrogenase 5 inhibitors, alpha 1 antitrypsin stimulators, alpha 1 proteinase inhibitors, androgen receptor regulators, angiotensin converting enzyme 2 stimulators, AN P agonists, Bcr protein inhibitors, β1 adrenergic receptor antagonists, β2 adrenergic receptor antagonists, β2 adrenergic receptor regulators, β amyloid regulators, BMP10 gene inhibitors, BMP15 gene inhibitors, calcium channel inhibitors, cathepsin G inhibitors, CCL26 gene inhibitors, CCR3 chemokine regulators, CCR4 chemokine antagonists, cell adhesion molecule inhibitors, chaperonin stimulators, chitinase inhibitors, collagen I antagonists, Complement C3 inhibitors, CSF-1 antagonists, CXCR2 chemokine antagonists, cytokine receptor common beta chain regulators, cytotoxic T-lymphocyte protein-4 stimulators, deoxyribonuclease I stimulators, deoxyribonuclease stimulators, dipeptidyl peptidase I inhibitors, DNA gyrase inhibitors, DP prostanoid receptor regulators, E-selectin antagonists, EGFR family tyrosine kinase receptor inhibitors, elastin regulators, endothelin ET -A antagonists, endothelin ET-B antagonists, epoxide hydrolase inhibitors, FGF3 receptor antagonists, Fyn tyrosine kinase inhibitors, GATA3 transcription factor inhibitors, glucosylceramidase regulators, glutamate receptor regulators, GM-CSF ligand inhibitors, guanylate cyclase stimulators, H+K+ATPase inhibitors, hemoglobin regulators, heparin agonists, histone deacetylase inhibitors, histone deacetylase-2 stimulators, HMG CoA reductase inhibitors, I-kappa B kinase beta inhibitors, ICAM1 gene inhibitors, IL-17 antagonists, IL-17 receptor regulators, IL-23 antagonists, IL-4 receptor regulators, immunoglobulin G regulators, immunoglobulin G1 agonists,Immunoglobulin G1 regulators, Immunoglobulin epsilon Fc receptor IA antagonists, Immunoglobulin gamma Fc receptor IIB antagonists, Immunoglobulin kappa regulators, Insulin sensitizers, Interferon beta ligands, Interleukin 1-like receptor antagonists, Interleukin 18 ligand inhibitors, Interleukin receptor 17A antagonists, Interleukin-1 beta ligand inhibitors, Interleukin-5 ligand inhibitors, Interleukin-6 ligand inhibitors, KCNA voltage-dependent potassium channel-3 inhibitors, Kit ligand inhibitors, Laminin-5 agonists, Leukotriene CysLT1 receptor antagonists, Leukotriene CysLT2 receptor agonists antagonists, LOXL2 gene inhibitors, Lyn tyrosine kinase inhibitors, MARCKS protein inhibitors, MDR-related protein 4 inhibitors, metalloprotease-2 regulators, metalloprotease-9 regulators, mineralocorticoid receptor antagonists, muscarinic M2 receptor antagonists, muscarinic M4 receptor antagonists, muscarinic M5 receptor antagonists, natriuretic peptide receptor A agonists, natural killer cell receptor regulators, nicotinic ACh receptor alpha 7 subunit stimulators, NK cell receptor regulators, nuclear factor kappa B regulators, opioid growth factor receptor agonists, P-glycoprotein inhibitors, P2X3 purinergic receptor antagonists, p38 MAP kinase inhibitors, peptidase 1 regulators, phospholipase A2 inhibitors, phospholipase C inhibitors, plasminogen activator inhibitor 1 inhibitors, platelet activating factor receptor antagonists, PPARγ agonists, prostacyclin agonists, protein tyrosine kinase inhibitors, SH2 domain inositol phosphatase 1 stimulators, signal transduction inhibitors, sodium channel inhibitors, STAT-3 regulators, stem cell antigen-1 inhibitors, superoxide dismutase regulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 inhibitors, TGFβ agonists, TGFβ antagonists, thromboxane synthetase inhibitors, thymic stromal lymphoid protein ligand inhibitors, thymosin agonists, thymosin beta 4 ligands, TLR-8 agonists, TLR-9 agonists, TLR9 gene stimulators,These include, but are not limited to, topoisomerase IV inhibitors, troponin I fast skeletal muscle stimulators, troponin T fast skeletal muscle stimulators, type I IL-1 receptor antagonists, type II TNF receptor modulators, ion channel modulators, uteroglobin stimulators, and VIP agonists.

[0115] Specific agents that may be used in combination with the JAK inhibitor compounds of the invention include rociptol acetate, umeclidinium bromide, secukinumab, metenkephalin acetate, tridecactide acetate, fluticasone propionate, alpha-cyclodextrin stabilized sulforaphane, tezepelumab, mometasone furoate, BI-1467335, dupilumab, aclidinium, formoterol, AZD-1419, HI-1640V, rivipancel, CMP-001, mannitol, ANB-020, omalizumab, tregalizumab, Mitizax, ben Ralizumab, Golimumab, Roflumilast, Imatinib, REGN-3500, Masitinib, Apremilast, RPL-554, Actimmune, Adalimumab, Rupatadine, Parogrel, MK-1029, Beclomethasone Dipropionate, Formoterol Fumarate, Mogamulizumab, Seratrodast, UCB-4144, Nemiralisib, CK-2127107, Fevipiprant, Danilixin, Bosentan, Abatacept, EC-18, Duvelisib, Dosiparstat, Ciprofloxacin, Salbutamol HFA, Erdosteine, Pr EP-001, nedocromil, CDX-0158, salbutamol, enobosarm, R-TPR-022, lenzilumab, fluticasone furoate, vilanterol triphenylacetate, fluticasone propionate, salmeterol, PT-007, PRS-060, remestemcel-L, citrulline, RPC-4046, nitric oxide, DS-102, gerilimuzumab, Actair, fluticasone furoate, umeclidinium, vilanterol, AG-NPP709, Gamunex, infliximab, Ampion, acumpimod, canakinumab, I NS-1007, CYP-001, sirukumab, fluticasone propionate, mepolizumab, pitavastatin, solithromycin, etanercept, ivacaftor, anakinra, MPC-300-IV, glycopyrronium bromide, aclidinium bromide, FP-025, risankizumab, glycopyrronium, formoterol fumarate, Adipocell, YPL-001, tiotropium bromide, glycopyrronium bromide, indacaterol maleate, andecaliximab, olodaterol, esomeprazole, dust mite vaccine,Artemisia pollen allergen vaccine, vamorolone, gefapixant, rebefenacin, gefitinib, ReJoin, tipelukast, bedoradrine, SCM-CGH, ​​SHP-652, RNS-60, brodalumab, BIO-11006, umeclidinium bromide, vilanterol triphenylacetate, ipratropium bromide, tralokinumab, PUR-1800, VX-561, VX-371, olopatadine, tulobuterol, formoterol fumarate, triamcinolone acetonide, reslizumab, salmeterol xinafoate, flupropionate Ticason, beclomethasone dipropionate, formoterol fumarate, tiotropium bromide, ligelizumab, RUTI, bertilimumab, omalizumab, glycopyrronium bromide, SENS-111, beclomethasone dipropionate, CHF-5992, LT-4001, indacaterol, glycopyrronium bromide, mometasone furoate, fexofenadine, glycopyrronium bromide, azithromycin, AZD-7594, formoterol, CHF-6001, batefenterol, OATD-01, olodaterol, CJM-112, Rosi Glitazones, salmeterol, setiprant, inhaled interferon beta, AZD-8871, plecanatide, fluticasone, salmeterol, eicosapentaenoic acid monoglyceride, lebrikizumab, RG-6149, QBKPN, mometasone, indacaterol, AZD-9898, sodium pyruvate, zileuton, CG-201, imidafenacin, CNTO-6785, CLBS-03, mometasone, RGN-137, procaterol, formoterol, CCI-15106, POL-6014, indacaterol, beclomethasone, MV -130, GC-1112, Allergovac depot, MEDI-3506, QBW-251, ZPL-389, Udenafil, GSK-3772847, Levocetirizine, AXP-1275, ADC-3680, Timapiprant, Avesiterol, AZD-7594, Ipratropium bromide, Salbutamol sulfate, Tadequinig alfa, ACT-774312, Dornase alfa, Iloprost, Batefenterol, Fluticasone furoate, Alicaforsen, Ciclesonide, Emeramide, Arformoterol, SB-010, Ozagrel,BTT-1023, Dectrekumab, Levalbuterol, Pranlukast, Hyaluronic Acid, GSK-2292767, Formoterol, NOV-14, Lucinactant, Salbutamol, Prednisolone, Ebastine, Dexamethasone Cipecilate, GSK-2586881, BI-443651, GSK-2256294, VR-179, VR-096, hdm-ASIT+, Budesonide, GSK-2245035, VTX-1463, Emedastine, Dexpramipexole, Levalbuterol, N-6022, Dexamethasone Phosphate Samethasone sodium, PIN-201104, OPK-0018, TEV-48107, Suplatast, BI-1060469, Gemilukast, Interferon gamma, Darazatide, Bilastine, Fluticasone propionate, Salmeterol xinafoate, RP-3128, Bencycloquidium bromide, Reslizumab, PBF-680, CRTH2 antagonist, Pranlukast, Salmeterol xinafoate, Fluticasone propionate, Tiotropium bromide monohydrate, Macilukast, RG-7990, Doxofyllin e, abesiterol, glycopyrronium bromide, TEV-46017, ASM-024, fluticasone propionate, glycopyrronium bromide, salmeterol xinafoate, salbutamol, TA-270, flunisolide, sodium cromoglicate, Epsi-gam, ZPL-521, salbutamol, aviptadil, TRN-157, zafirlukast, stempeucel, pemirolast sodium, nadolol, fluticasone propionate + salmeterol xinafoate, RV-1729, salbutamol sulfate, carbon dioxide + perfluor rooctyl bromide, APL-1, dextrecumab + VAK-694, acetylsalicylic lysine, zileuton, TR-4, human allogeneic adipose-derived mesenchymal progenitor cell therapy, MEDI-9314, PL-3994, HMP-301, TD-5471, NKTT-120, pemirolast, beclomethasone dipropionate, trantinterol, alphaluminol monosodium, IMD-1041, AM-211, TBS-5, ARRY-502, seratrodast, recombinant midismase, ASM-8, deflazacort, bambuterol, RBx-10017609,These include, but are not limited to, ipratropium + fenoterol, fluticasone + formoterol, epinastine, WIN-901X, VALERGEN-DS, OligoG-COPD-5 / 20, tulobuterol, oxis Turbuhaler, DSP-3025, ASM-024, mizolastine, budesonide + salmeterol, LH-011, AXP-E, histamine human immune globulin, YHD-001, theophylline, ambroxol + erdosteine, ramatroban, montelukast, pranlukast, AG-1321001, tulobuterol, ipratropium + salbutamol, tranilast, methylprednisolone suleptanate, colforsin daropate, repirinast, and doxofylline.

[0116] Also provided herein is a pharmaceutical composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt thereof and one or more other therapeutic agents.The therapeutic agent may be selected from the classes of agents identified above and from the list of specific agents described above.In some embodiments, the pharmaceutical composition is suitable for pulmonary delivery.In some embodiments, the pharmaceutical composition is suitable for inhalation or nebulization administration.In some embodiments, the pharmaceutical composition is a dry powder or a liquid composition.

[0117] Additionally, the present disclosure provides a method of treating a disease or disorder in a mammal (e.g., a human), comprising administering to the mammal (or human) a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, and one or more other therapeutic agents.

[0118] When used in combination therapy, the active agents may be formulated in a single pharmaceutical composition, or the active agents may be provided in separate compositions that are administered at the same time or at different times by the same or different administration routes.Such compositions may be packaged separately, or may be packaged together as a kit.Two or more therapeutic agents in the kit may be administered by the same or different administration routes. EXAMPLES

[0119] The following synthetic and biological examples are offered to illustrate the invention and are not to be construed in any way as limiting the scope of the invention. In the examples below, the following abbreviations have the following meanings unless otherwise indicated. Abbreviation not defined below have their generally accepted meanings.

[0120] Abbreviation ACN = acetonitrile Bis(pinacolato)diboron = 4,4,5,5,4',4',5',5'-octamethyl[2,2']bi[[1,3,2]dioxaborolanyl] Calcd = calculated value DCM = dichloromethane DIPEA = N,N-diisopropylethylamine DMA = Dimethylacetamide DMSO = dimethyl sulfoxide DMF = N,N-dimethylformamide PdCl 2( dppf) = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Eq = equivalent EtOAc = ethyl acetate h = time HATU = N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HBTU = N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate IPA = Isopropyl alcohol MeOH = methanol min = minutes NaHMDS = sodium bis(trimethylsilyl)amide NBS = N-bromosuccinimide Pd(PPh3)4 = Tetrakis(triphenylphosphine)palladium(0) RT = room temperature SEM = 2-(trimethylsilyl)ethoxymethyl SEMCl = 2-(trimethylsilyl)ethoxymethyl chloride TBAF = Tetra-N-butylammonium fluoride TBDPSCl = tert-butyl(chloro)diphenylsilane TEA = triethylamine TFA = trifluoroacetic acid THF = Tetrahydrofuran THP = tetrahydropyran

[0121] Reagents and solvents were purchased from commercial suppliers (Aldrich, Fluka, Sigma, etc.) and used without further purification. The progress of reaction mixtures was monitored by thin layer chromatography (TLC), analytical high performance liquid chromatography (anal. HPLC) and mass spectrometry. Reaction mixtures were worked up as specifically described in each reaction. Usually, reaction mixtures were purified by extraction and other purification methods such as temperature- and solvent-dependent crystallization and precipitation. In addition, reaction mixtures were routinely purified by column chromatography or preparative HPLC, typically using C18 or BDS column packings and conventional eluents. Representative preparative HPLC conditions are described below.

[0122] Characterization of the reaction products was performed using mass spectrometry and 1 H-NMR spectroscopy was routinely used. For NMR analysis, samples were dissolved in deuterated solvents (e.g., CD3OD, CDCl3 or d6-DMSO) and analyzed using a Varian Gemini 2000 instrument (400 MHz) under standard observation conditions. 1H-NMR spectra were acquired. Mass spectrometric identification of compounds was performed by electrospray ionization (ESMS) using a model API 150 EX instrument from Applied Biosystems (Foster City, CA) or a 3100 instrument from Waters (Milford, MA) linked to an automated purification system.

[0123] Preparative HPLC conditions Column: C18, 5μm. 21.2×150mm or C18, 5μm 21×250 or C14, 5μm 21×150mm Column temperature: room temperature Flow rate: 20.0mL / min Mobile phase: A=water+0.05%TFA B=ACN+0.05% TFA, Injection volume: (100-1500μL) Detector wavelength: 214nm

[0124] Crude compound was dissolved in 1:1 water:acetic acid at approximately 50 mg / mL. A 4 minute analytical scale test run was performed using a 2.1 x 50 mm C18 column followed by a 15 or 20 minute preparative scale run using a 100 μL injection with a gradient based on the %B retention of the analytical scale test run. The exact gradient was sample dependent. Samples containing close running impurities were examined using a 21 x 250 mm C18 column and / or a 21 x 150 mm C14 column for best separation. Fractions containing the desired product were identified by mass spectrometry.

[0125] Preparation of (2-((3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (I-7) [ka]

[0126] (a) (2-((3-ethylphenoxy)methoxy)ethyl)trimethylsilane (I-5) To a stirred solution of 3-ethylphenol (I-4) (200 g, 1.64 mol) in DMF (1.50 L) cooled to 0 °C, NaH (78.6 g, 1.96 mol) was added in portions. The reaction mixture was then stirred at 0 °C for 1 h. SEMCl (300 g, 1.80 mol) was then added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. TLC indicated complete consumption of starting material. The reaction mixture was quenched with ice water (2.0 L) and extracted with ethyl acetate (2 × 1.0 L). The combined organic layers were washed with brine solution (1.0 L), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (5-10% EtOAc in heptane) to give the desired product as a clear liquid (305 g, 74% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J = 7.8 Hz, 1H), 6.88 - 6.77 (m, 3H), 5.20 (s, 2H), 3.69 (t, J = 8.0 Hz, 2H), 2.56 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H), 0.88 (t, J = 8.1 Hz, 2H), 0.00 (s, 9H).

[0127] (b) (2-((4-bromo-3-ethylphenoxy)methoxy)ethyl)trimethylsilane (I-6) To a stirred solution of I-5 (200 g, 792 mmol) in ACN (1.40 L) cooled to 0° C., NBS (141 g, 792 mmol) was added in portions over 30 min. The resulting reaction mixture was stirred at room temperature for 2 h. TLC indicated complete consumption of starting material. The reaction mixture was poured into ice-cold water (1 L) and extracted with EtOAc (2×1 L). The combined organic layers were washed with water (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (100% heptane) to give the desired product (230 g, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.44 (dd, J = 8.8, 1.9 Hz, 1H), 6.99 (d, J = 2.9 Hz, 1H), 6.81 (dt, J = 8.8, 2.6 Hz, 1H), 5.21 (d, J = 2.0 Hz, 2H), 3.73 - 3.64 (m, 2H), 2.63 (qd, J = 7.5, 2.0 Hz, 2H), 1.14 (td, J = 7.6, 1.9 Hz, 3H), 0.95 - 0.79 (m, 2H), 0.00 (s, 9H).

[0128] (c) (2-((3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (I-7) To a stirred solution of I-6 (100 g, 302 mmol) in 1,4-dioxane (1.00 L) was added bis(pinacolato)diboron (76.6 g, 302 mmol) and potassium acetate (59.2 g, 604 mmol). The reaction mixture was degassed with nitrogen for 15 min, then PdCl2(dppf).DCM (24.6 g, 30.2 mmol) was added. The reaction mixture was stirred and heated at 110 °C under nitrogen for 16 h. TLC indicated complete consumption of starting material. The reaction mixture was diluted with EtOAc (1 L) and washed with water (1 L). The combined organic layers were separated, dried over Na2SO4, and concentrated. The crude mixture was purified by silica gel column chromatography (0-10% EtOAc in heptane) to give the desired product as a yellow liquid (75.0 g, 66% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 8.1 Hz, 1H), 6.87 - 6.77 (m, 2H), 5.21 (d, J = 13.2 Hz, 2H), 3.69 (t, J = 8.0 Hz, 2H), 2.80 (q, J = 7.5 Hz, 2H), 1.27 (s, 12H), 1.11 (t, J = 7.5 Hz, 3H), 0.91 - 0.84 (m, 2H), 0.00 (s, 9H).

[0129] Preparation of 3-(1-benzyl-1H-imidazol-2-yl)-6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-12) [ka]

[0130] (a) 4-Bromo-2-fluorobenzoyl chloride (I-9) To a stirred solution of 4-bromo-2-fluorobenzoic acid (I-8) (50.0 g, 228 mmol) in DCM (300 mL) and DMF (4.0 mL) was added oxalyl chloride (96.57 mL, 913 mmol) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction (monitored by TLC, checked by quenching with MeOH), the reaction was concentrated under reduced pressure (under nitrogen) to give an off-white solid (54.2 g), which was used in the next step without further purification.

[0131] (b) (1-benzyl-1H-imidazol-2-yl)(4-bromo-2-fluorophenyl)methanone (I-10) To a stirred solution of 1-benzyl-1H-imidazole (30.0 g, 190 mmol) in acetonitrile (165 mL) was added triethylamine (133.4 mL, 949 mmol) at room temperature. Compound I-9 (54.2 g, 228 mmol) was taken separately in acetonitrile (165 ml) and added to the reaction mixture. The reaction was stirred at room temperature for 2 h. TLC indicated consumption of starting material. The reaction was quenched with cold water (500 mL) and extracted with ethyl acetate (2×600 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. It was purified by silica gel column chromatography (10% EtOAc in heptane) to give the desired product as an off-white solid (79.0 g, 58% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.68 (dd, J = 9.7, 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.54 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (dd, J = 8.1, 6.5 Hz, 2H), 7.32 - 7.26 (m, 1H), 7.25 (s, 1H), 7.22 (dd, J = 6.9, 1.8 Hz, 2H), 5.70 (s, 2H).(m / z):[M+H] + C 17 H 13 Calculated value for BrFN2O: 359.02; measured value: 358.97.

[0132] (c) 3-(1-benzyl-1H-imidazol-2-yl)-6-bromo-1H-indazole (I-11) To a stirred solution of I-10 (53.0 g, 147.5 mmol) in DMSO (105 mL) was added hydrazine hydrate (72.5 mL, 1475.5 mmol) dropwise at room temperature. The reaction mixture was stirred at 90° C. for 3 h. After 3 h, TLC showed complete consumption of starting material. The reaction mixture was diluted with ice-cold water (800 mL) and a precipitate was observed. The reaction was filtered and washed with ice-cold water (500 mL) to give the desired product as an off-white solid (47.0 g, 90% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.40 (s, 1H), 7.35 (dd, J = 8.6, 1.7 Hz, 1H), 7.29 (dd, J = (m / z):[M+H] + C 17 H 14 Calculated value for BrN4: 353.04, measured value: 353.03.

[0133] (d) 3-(1-benzyl-1H-imidazol-2-yl)-6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-12) To a stirred solution of I-11 (47.0 g, 133.1 mmol) in ethyl acetate (350 mL) at 0° C., TFA (30.5 mL, 399.1 mmol) was added. Dihydropyran (60.8 mL, 665.3 mmol) was added dropwise. The reaction mixture was then heated to 80° C. and stirred for 2 days. After 2 days, TLC showed complete consumption of starting material. The reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (2×900 mL). The combined organic layers were further washed with saturated aqueous NaHCO3 (800 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (5% EtOAc in heptane) to give the desired product as an off-white solid (40 g, 69% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H), 7.42 (dd, J = 8.6, 1.6 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.25 - 7.19 (m, 3H), 7.19 (d, J = 1.2 Hz, 1H), 5.94 (dd, J = 8.9, 2.5 Hz, 1H), 5.86 (d, J = 15.3 Hz, 1H), 5.77 (d, J = 15.3 Hz, 1H), 3.78 (tp, J = 11.6, 3.8 Hz, 2H), 2.38 - 2.25 (m, 1H), 2.04 - 1.89 (m, 2H), 1.70 (dtt, J = 11.5, 8.5, 4.0 Hz, 1H), 1.62 - 1.45 (m, 2H).(m / z):[M+H] + C 22 H 22 Calculated value for BrNO: 437.10; measured value: 437.11.

[0134] Preparation of 6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1H-indazole (I-15) [ka]

[0135] (a) 3-(1-benzyl-1H-imidazol-2-yl)-6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-13) To a stirred solution of I-12 (60.0 g, 137 mmol) and I-7 (62.3 g, 165 mmol) in dioxane (360 mL) and water (90.0 mL) was added K3PO4 (87.4 g, 412 mmol). The reaction mixture was purged with argon for 15 min, and then Pd(PPh3)4 (15.9 g, 13.7 mmol) was added to it. The reaction was then heated to 110 °C and stirred for 3 h. TLC indicated consumption of starting material. The reaction mixture was diluted with water (600 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were then washed with brine (600 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. It was purified by silica gel column chromatography (10% EtOAC in heptane). The desired product was isolated as a clear liquid (65 g, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.47 (s, 1H), 7.34 - 7.27 (m, 2H), 7.27 - 7.20 (m, 3H), 7.20 - 7.14 (m, 3H), 7.01 (d, J = 2.6 Hz, 1H), 6.94 (dd, J = 8.4, 2.6 Hz, 1H), 5.98 - 5.87 (m, 2H), 5.85 - 5.74 (m, 1H), 5.27 (s, 2H), 3.82 (d, J = 11.4 Hz, 1H), 3.72 (q, J = 10.1, 9.0 Hz, 3H), 2.55 (t, J = 7.5 Hz, 2H), 2.35 (s, 1H), 1.98 (s, 2H), 1.79 - 1.64 (m, 1H), 1.55 (s, 2H), 1.04 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 8.1 Hz, 2H), 0.00 (s, 9H).(m / z):[M+H] + C 36 H 45 Calculated value of N4O3Si: 609.33, measured value: 609.38.

[0136] (b) 6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-(1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-14) To a stirred solution of I-13 (65.0 g, 107 mmol) in isopropanol (450 mL) and THF (150.0 mL) was added 20% Pd(OH)2 / C (60.0 g, 84.5 mmol). The reaction mixture was subjected to hydrogenation using a H2 balloon and stirred at room temperature for 16 h. TLC showed complete consumption of starting material. The reaction mixture was filtered through a pad of Celite, washed with EtOAc (500 mL), and the filtrate was concentrated under reduced pressure to give the desired crude product (53.0 g, 96% yield) as a colorless liquid, which was used directly in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.23 (s, 1H), 7.19 (dd, J = 8.3, 3.7 Hz, 2H), 7.14 (s, 1H), 7.01 (s, 1H), 6.95 (d, J = 9.4 Hz, 1H), 5.95 (d, J = 9.8 Hz, 1H), 5.27 (s, 2H), 3.93 (d, J = 12.0 Hz, 1H), 3.74 (t, J = 8.1 Hz, 3H), 2.56 (d, J = 7.6 Hz, 2H), 2.03 (s, 2H), 1.76 (s, 1H), 1.58 (s, 2H), 1.05 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 8.1 Hz, 2H), 0.00 (s, 9H).(m / z):[M+H] + C 29 H 39 Calculated value of N4O3Si: 519.28, measured value: 519.28.

[0137] (c) 6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1H-indazole (I-15) To a stirred solution of I-14 (43.0 g, 82.9 mmol) in DMF (400 mL) was added sodium hydride 60% (w / w) (4.97 g, 124 mmol) at 0° C. The reaction mixture was then stirred at 0° C. for 20 min. Then, SEMCl (17.6 mL, 99.5 mmol) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. TLC indicated complete consumption of starting material. The reaction mixture was quenched with ice water (1 L) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water (800 mL) and brine (800 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude compound. It was purified by silica gel column chromatography (15% EtOAc in heptane). The desired product was isolated as an off-white solid (42.0 g, 66% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.50 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.26 (s, 2H), 7.25 - 7.19 (m, 2H), 7.02 (s, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.09 (d, J = 10.5 Hz, 1H), 5.93 (d, J = 10.5 Hz, 1H), 5.75 (d, J = 9.0 Hz, 1H), 5.28 (s, 2H), 4.03 (d, J = 11.5 Hz, 1H), 3.81 (t, J = 8.4 Hz, 2H), 3.74 (t, J = 10.0 Hz, 2H), 3.63 (d, J = 8.5 Hz, 1H), 3.58 (t, J = 8.2 Hz, 2H), 2.59 (q, J = 7.5 Hz, 3H), 2.13 (d, J = 16.5 Hz, 2H), 1.83 - 1.70 (m, (m / z):[M+H] + C 35 H 53Calculated value of N4O4Si2: 649.36, measured value: 649.49.

[0138] Preparation of 4-(3-(4-bromo-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-3-ethylphenol (I-17) [ka]

[0139] (a) 3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-16) NBS (2.74 g, 15.4 mmol) was taken in DCM (100 mL) and added dropwise to a stirred solution of I-15 (10.0 g, 15.4 mmol) in DCM (400 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 5 min. TLC showed complete consumption of starting material. The reaction mixture was quenched with ice water (300 mL) and extracted with DCM (2 × 250 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give the crude product. It was purified by silica gel column chromatography (8-10% EtOAc in heptane). The desired product was isolated as a colorless amorphous solid (9.10 g, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 7.32 (s, 1H), 7.19 (dd, J = 13.4, 8.4 Hz, 2H), 7.01 (d, J = 2.5 Hz, 1H), 6.95 (dd, J = 8.4, 2.5 Hz, 1H), 6.09 - 5.94 (m, 3H), 5.27 (s, 2H), 3.89 (d, J = 11.4 Hz, 1H), 3.78 (d, J = 5.7 Hz, 1H), 3.74 (t, J = 8.1 Hz, 2H), 3.52 (dt, J = 16.0, 8.0 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 2.44 (s, 1H), 2.05 (d, J = 11.1 Hz, 2H), 1.77 (s, 1H), 1.59 (s, 2H), 1.23 (s, 1H), 1.03 (t, J = 7.5 Hz, 2H), 0.92 (t, J = 8.1 Hz, 2H), 0.84 (td, J = 10.5, 9.0, 5.4 Hz, 2H), 0.00 (m, 9H), -0.19 (s, 9H).(m / z):[M+H] + C 35 H 52 Calculated value for BrN4O4Si2: 727.27; measured value: 727.58.

[0140] (b) 4-(3-(4-bromo-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-3-ethylphenol (I-17) To a stirred solution of I-16 (32.0 g, 44.0 mmol) in THF (100 mL) was added TBAF (1 M in THF) (448 mL, 448 mmol) at room temperature. The reaction mixture was then heated to 80° C. and stirred for 2 days. TLC showed complete consumption of the starting material. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (3×300 mL) and brine (300 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (20% EtOAc in heptane) to give the desired product as an off-white solid (13.7 g, 66% yield). 1 H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.43 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.64 (s, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.4, 1.3 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.69 (dd, J = 8.2, 2.5 Hz, 1H), 5.96 (dd, J = 10.0, 2.4 Hz, 1H), 3.92 (d, J = 11.4 Hz, 1H), 3.77 (dt, J = 11.5, 6.9 Hz, 1H), 2.07 (s, 2H), 2.03 (s, 1H), 1.76 (s, 1H), 1.58 (p, J = 5.0 Hz, 2H), 1.04 (t, J = 7.5 Hz, 3H).(m / z):[M+H] + C 23 H 24 Calculated value for BrN4O2: 469.11, measured value: 469.36.

[0141] Preparation of 3-(1-benzyl-1H-imidazol-2-yl)-6-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-22) [ka]

[0142] (a) 4-Bromo-2,3-difluorobenzoyl chloride (I-19) To a stirred solution of 4-bromo-2,3-difluorobenzoic acid (I-18) (28.0 g, 118 mmol) in DCM (300 mL) and DMF (915 μL, 0.1 equiv, 11.8 mmol) was added dropwise oxalyl chloride (40.5 mL, 473 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC, checked by quenching with MeOH), the reaction was concentrated under reduced pressure (under nitrogen) to give an off-white solid (31.0 g), which was used in the next step without further purification.

[0143] (b) (1-benzyl-1H-imidazol-2-yl)(4-bromo-2,3-difluorophenyl)methanone (I-20) To a stirred solution of compound I-19 (16.0 g, 101 mmol) in acetonitrile (100 ml) was added triethylamine (51.2 g, 506 mmol). 1-Benzyl-1H-imidazole (31.0 g, 121 mmol) was separately dissolved in acetonitrile (100 mL) and added to the reaction mixture at room temperature. The reaction was stirred at room temperature for 2 h. TLC indicated consumption of starting material. The reaction was quenched with cold water (500 mL) and extracted with ethyl acetate (2×600 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. It was purified by silica gel column chromatography (10–15% EtOAc in heptane) to give the desired product as a light yellow solid (28.0 g, 73% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.66 (ddd, J = 8.1, 5.9, 1.8 Hz, 1H), 7.46 (ddd, J = 8.4, 6.4, 2.0 Hz, 1H), 7.36 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H), 7.28 (s, 2H), 7.23 (d, J = 6.9 Hz, 2H), 5.70 (s, 2H).(m / z):[M+H] + C 17 H 12 The calculated value for BrF2N2O is 377.01, and the measured value is 374.94.

[0144] (c) 3-(1-benzyl-1H-imidazol-2-yl)-6-bromo-7-fluoro-1H-indazole (I-21) To a stirred solution of I-20 (21.7 g, 57.5 mmol) in DMSO (120 mL) was added hydrazine hydrate (28.0 mL, 575 mmol) dropwise at room temperature. The reaction mixture was stirred at 90° C. for 3 h. After 3 h, TLC showed complete consumption of starting material. The reaction mixture was diluted with ice-cold water (2×500 mL) and a precipitate was observed. The reaction was filtered and washed with ice-cold water (500 mL) to give the desired product as an off-white solid (20.0 g, 87% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.7 Hz, 1H), 7.43 (s, 1H), 7.40 (dd, J = 8.6, 5.8 Hz, 1H), 7.30 (t, J = 7.3 Hz, 2H), 7.24 (d, J = 7.1 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 7.18 (s, 2H), 5.84 (s, 2H).(m / z):[M+H] + C 17 H 13 Calculated value for BrFN4: 373.03, measured value: 372.94.

[0145] (d) 3-(1-benzyl-1H-imidazol-2-yl)-6-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-22) To a stirred solution of I-21 (20.0 g, 53.9 mmol) in ethyl acetate (350 mL) was added TFA (12.4 mL, 162 mmol). At 0 °C, dihydropyran (23.6 mL, 269 mmol) was added dropwise. The reaction mixture was then heated to 80 °C and stirred for 2 days. After 2 days, TLC showed complete consumption of starting material. The reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (2 × 300 mL). The combined organic layers were further washed with saturated aqueous NaHCO3 (800 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (8-10% EtOAc in heptane) to give the desired product as an off-white solid (19.5 g, 78% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d, J = 8.6 Hz, 1H), 7.52 (s, 1H), 7.49 (dd, J = 8.6, 5.6 Hz, 1H), 7.30 (dd, J = 8.0, 6.5 Hz, 2H), 7.24 (d, J = 6.6 Hz, 1H), 7.21 (d, J = 2.9 Hz, 2H), 7.19 (s, 1H), 5.87 (dd, J = 6.9, 2.4 Hz, 1H), 5.86 (d, J = 15.3 Hz, 1H), 5.77 (d, J = 15.3 Hz, 1H), 3.87 - 3.80 (m, 1H), 3.65 (td, J = 11.1, 3.3 Hz, 1H), 2.36 - 2.27 (m, 1H), 2.01 (s, 1H), 1.75 - 1.67 (m, 1H), 1.61 - 1.42 (m, 1H).(m / z):[M+H] + C 22 H 21 Calculated value for BrFN4O: 455.09; measured value: 455.06.

[0146] Preparation of 6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1H-indazole (I-25) [ka]

[0147] (a) 3-(1-benzyl-1H-imidazol-2-yl)-6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-23) To a stirred solution of I-22 (19.5 g, 42.8 mmol) and I-7 (17.8 g, 47.1 mmol) in dioxane (200 mL) and water (20.0 mL) was added K3PO4 (27.3 g, 128 mmol). The reaction mixture was purged with argon for 5 min, and then PdCl2(dppf).DCM (3.49 g, 4.28 mmol) was added to it. The reaction was then heated to 100 °C and stirred for 16 h. TLC indicated consumption of starting material. The reaction mixture was then filtered through a celite pad and the residue was washed with ethyl acetate (2 x 200 mL). The combined organics were then washed with cold water (300 mL) and brine (300 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. It was purified by silica gel column chromatography (12% EtOAC in heptane). The desired product was isolated as a clear amorphous solid (20.0 g, 73% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.30 (d, J = 7.2 Hz, 2H), 7.25 (d, J = 6.3 Hz, 2H), 7.22 (d, J = 3.6 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 2.6 Hz, 1H), 6.95 (dd, J = 8.5, 2.6 Hz, 1H), 5.94 - 5.84 (m, 2H), 5.80 (d, J = 15.4 Hz, 1H), 5.28 (s, 2H), 3.84 (s, 1H), 3.74 (t, J = 8.1 Hz, 2H), 3.58 (d, J = 11.9 Hz, 1H), 2.04 (d, J = 14.0 Hz, 2H), 1.69 (s, 1H), 1.53 (s, 2H), 1.44 (s, 1H), 1.24 (s, 1H), 0.99 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 8.1 Hz, 2H), 0.88 - 0.79 (m, 2H), 0.00 (s, 9H).(m / z):[M+H] + C 36 H 44 Calculated value of FN4O3Si: 627.32, measured value: 627.54.

[0148] (b) 6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-7-fluoro-3-(1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-24) To a stirred solution of I-23 (20.0 g, 31.9 mmol) in isopropanol (200 mL) and THF (50.0 mL) was added 20% Pd(OH)2 / C (20.0 g, 163 mmol). The reaction mixture was subjected to hydrogenation using a H2 balloon and stirred at room temperature for 5 h. TLC showed complete consumption of starting material. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to give the crude desired product (18.0 g, 71% yield) as a clear amorphous solid, which was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d, J = 8.2 Hz, 1H), 7.25 (s, 2H), 7.18 (d, J = 8.3 Hz, 1H), 7.12 (dd, J = 8.3, 5.9 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.4, 2.6 Hz, 1H), 5.90 (d, J = 9.4 Hz, 1H), 5.76 (s, 1H), 5.29 (s, 2H), 3.95 (d, J = 11.6 Hz, 1H), 3.75 (t, J = 8.1 Hz, 2H), 3.65 (s, 1H), 2.44 (s, 2H), 2.09 (d, J = 13.8 Hz, 2H), 1.75 (s, 1H), 1.57 (s, 2H), 1.44 (s, 1H), 1.01 (t, J = 7.5 Hz, 3H), 0.91 (d, J = 8.1 Hz, 2H), 0.00 (s, 9H).(m / z):[M+H] + C 29 H 38 Calculated value of FN4O3Si: 537.27, measured value: 537.36.

[0149] (c) 6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1H-indazole (I-25) To a stirred solution of I-24 (18.0 g, 33.5 mmol) in DMF (180 mL) was added sodium hydride (2.81 g, 70.3 mmol) at 0 °C. The reaction mixture was then stirred at 0 °C for 30 min. After that, SEMCl (8.39 g, 50.3 mmol) was then added dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. TLC indicated complete consumption of starting material. The reaction mixture was quenched with ice water (300 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with water (400 mL) and brine (400 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude compound. It was purified by silica gel column chromatography (20-25% EtOAc in heptane). The desired product was isolated as an off-white solid (18.0 g, 71% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 8.3 Hz, 1H), 7.53 (s, 1H), 7.21 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.12 (dd, J = 8.3, 5.9 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.4, 2.6 Hz, 1H), 5.99 - 5.88 (m, 3H), 5.29 (s, 2H), 3.92 (d, J = 11.4 Hz, 1H), 3.75 (t, J = 8.1 Hz, 2H), 3.67 (d, J = 12.9 Hz, 1H), 3.51 (t, J = 8.0 Hz, 2H), 2.43 (s, 3H), 2.19 - 2.11 (m, 1H), 2.06 (s, 1H), 1.76 (d, J = 13.7 Hz, 2H), 1.57 (s, 2H), 1.00 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 8.1 Hz, 2H), 0.80 (t, J = 8.0 Hz, 2H), 0.00, (s, 9H), -0.15 (s, 9H).(m / z):[M+H] + C 35 H 52 Calculated value of FN4O4Si2: 667.35, measured value: 667.47.

[0150] Preparation of 3-ethyl-4-(3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl)phenol (I-27) [ka]

[0151] (a) 3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-ethyl-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-26) NBS (1.60 g, 9.0 mmol) was taken in DCM (60 mL) and added dropwise to a stirred solution of I-25 (6.0 g, 9.0 mmol) in DCM (240 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 5 min. TLC showed complete consumption of starting material. The reaction mixture was quenched with water (100 mL) and extracted with DCM (2 × 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give the crude product. It was purified by silica gel column chromatography (8-10% EtOAc in heptane). The desired product was isolated as a colorless amorphous solid (5.0 g, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.14 (q, J = 7.6, 6.7 Hz, 2H), 7.03 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 5.98 (s, 1H), 5.92 (d, J = 9.6 Hz, 2H), 5.28 (s, 2H), 3.92 (d, J = 11.1 Hz, 1H), 3.74 (t, J = 8.0 Hz, 2H), 3.66 (s, 1H), 3.51 (t, J = 8.1 Hz, 2H), 2.44 (d, J = 8.1 Hz, 3H), 2.15 (d, J = 12.9 Hz, 1H), 2.06 (s, 1H), 1.77 (s, 1H), 1.57 (s, 2H), 0.99 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 8.0 Hz, 2H), 0.78 (t, J = 8.0 Hz, 3H), 0.00 (s, 9H), -0.17 (d, J = 1.9 Hz, 9H).(m / z):[M+H] + C 35 H 51 Calculated value for BrFN4O4Si2: 747.26, measured value: 747.26.

[0152] (b) 4-(3-(4-bromo-1H-imidazol-2-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-3-ethylphenol (I-27) To a stirred solution of I-26 (15.0 g, 20.1 mmol) in THF (30 mL) at 0 °C was added TBAF (1 M in THF) (52.0 mL, 18.5 mmol). The reaction mixture was then heated to 80 °C and stirred for 2 days. TLC indicated complete consumption of the starting material. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (20-25% EtOAc in heptane) to give the desired product as an off-white solid (5.25 g, 53% yield). 1 H NMR (400 MHz, DMSO-d6) 9.53 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.13 (dd, J = 8.3, 6.0 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 2.6 Hz, 1H), 6.70 (dd, J = 8.2, 2.6 Hz, 1H), 5.93 - 5.86 (m, 1H), 3.95 (d, J = 11.3 Hz, 1H), 3.65 (dt, J = 11.8, 6.6 Hz, 1H), 2.39 (d, J = 7.7 Hz, 3H), 2.09 (q, J = 10.0, 7.3 Hz, 3H), 1.75 (s, 1H), 1.57 (d, J = 8.6 Hz, 2H), 0.99 (t, J = 7.5 Hz, 3H).(m / z):[M+H] + C 23 H 23 Calculated value for BrFN4O2: 487.10, measured value: 487.35.

[0153] Preparation of tert-butyl (R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-33) [ka]

[0154] (a) tert-Butyl (2R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (I-29) To a solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.0 g, 43.2 mmol) (I-28) in THF (150 mL) at -10°C, 4-methylmorpholine (5.23 mL, 47.6 mmol) was added followed by dropwise addition of isobutyl chloroformate (6.18 mL, 47.6 mmol). The reaction mixture was then stirred at -10°C for 1 h. The reaction mixture was filtered and the filtrate was used directly in the next step. A solution of NaBH4 (8.18 g, 216 mmol) in water (30.0 mL) was added dropwise to the reaction mixture at 0°C. The reaction mixture was then left to stir overnight at room temperature. After 16 h, the reaction mixture was quenched by the addition of saturated ammonium chloride solution (100 ml) and then the solution was extracted with EtOAc (3 x 200 ml). The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography eluting with 60-70% EtOAc / heptane to give the product (I-29) as a white solid (8.0 g, 85% yield).

[0155] (b) tert-Butyl (2R,4R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (I-30) To a stirred solution of tert-butyl (2R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (10.0 g, 46.0 mmol) (I-29) in DMF (50.0 mL) was added 1H-imidazole (9.40 g, 138 mmol). A solution of TBDPSCl (12.5 mL, 46.0 mmol) in DMF (30.0 mL) was then added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with ice-cold water and extracted with EtOAc (3×80 mL). The combined organic layers were then washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography eluting in 20-30% EtOAc / heptane to give the product (I-30) as a colorless liquid (6.0 g, 25% yield).

[0156] (c) tert-Butyl (R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-oxopyrrolidine-1-carboxylate (I-31) To a solution of tert-butyl (2R,4R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (6.00 g, 13.2 mmol) (I-30) in DCM (70.0 mL) at 0° C., trichloro-1,3,5-triazinane-2,4,6-trione (3.37 g, 14.5 mmol) was added and the reaction mixture was stirred at 0° C. for 2 min. To this solution, TEMPO (206 mg, 1.32 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was then filtered through Celite and the pad was washed with DCM. The resulting organic filtrate was then washed with aqueous sodium carbonate and extracted with DCM (3×100 ml). The combined organic layers were then dried over sodium sulfate and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography eluting in 20-25% EtOAc / heptane to give the product (I-31) as a white solid (5.0 g, 84% yield).

[0157] (d) tert-Butyl (R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-32) To a stirred solution of tert-butyl (R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-oxopyrrolidine-1-carboxylate (5.0 g, 11.0 mmol) (I-31) in dry THF (50.0 mL) at −78° C. under nitrogen atmosphere, NaHMDS (1 M in THF) (14.3 mL, 14.3 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 45 min. Then, a solution of N-(5-chloropyridin-2-yl)-N-(methanesulfonyl)methanesulfonamide (5.63 g, 14.3 mmol) in dry THF (20.0 mL) was added dropwise at −78° C. The reaction mixture was slowly warmed to room temperature and stirred for 16 h, after which TLC showed consumption of starting material. The reaction mixture was then quenched by the addition of ice-cold water, and the resulting solution was extracted with EtOAc (3×120 ml). The combined organic layers were then dried over sodium sulfate and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography eluting in 12-15% EtOAc / heptane to give the product (I-32) as a colorless liquid (4.9 g, 73% yield).

[0158] (e) tert-Butyl (R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-33) To a stirred solution of tert-butyl (R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (4.90 g, 8.37 mmol) (I-32) and bis(pinacolato)diboron (1.70 g, 6.69 mmol) in 1,4-dioxane (50.0 mL) was added potassium acetate (2.46 g, 25.1 mmol). The reaction mixture was purged with nitrogen for 10 min, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (612 mg, 0.1 equiv, 837 μmol) was added and the reaction mixture was stirred at 110° C. for 5 h. The reaction mixture was then filtered through a Celite pad, the pad was washed with EtOAc (60 ml) and the resulting filtrate was concentrated under reduced pressure. The crude product was then purified by silica gel chromatography eluting with 5% EtOAc / heptane to give the product (I-33) as a pale yellow liquid (1.95 g, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.61 - 7.51 (m, 4H), 7.50 - 7.34 (m, 6H), 6.40 (d, J = 9.5 Hz, 1H), 4.55 (d, J = 19.0 Hz, 1H), 4.22 - 3.81 (m, 3H), 3.73 (dd, J = 26.8, 8.9 Hz, 1H), 1.43 (s, 5H), 1.30 (s, 4H), 1.23 (s, 12H), 0.93 (d, J = 4.9 Hz, 9H).

[0159] Preparation of tert-butyl (R)-2-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-42) [ka]

[0160] (a) 1-(tert-butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (I-35) To a stirred solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (20.0 g, 86.5 mmol) (I-34) in acetonitrile (200 mL) at 0° C., potassium carbonate (23.9 g, 173 mmol) was slowly added followed by methyl iodide (24.6 g, 173 mmol). The reaction mixture was heated at 80° C. until disappearance of starting material by TLC (16 h). The reaction mixture was diluted with ice-cold water and extracted with EtOAc (3 times). The combined organic layers were then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography eluting with 60-70% EtOAc / heptane to give the product (I-35) as an off-white solid (21.1 g, 99% yield).

[0161] (b) 1-(tert-butyl) 2-methyl(2R,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (I-36) To an ice-cold solution of 1-(tert-butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 40.8 mmol) (I-35) in dichloromethane (100 mL) was added imidazole (8.33 g, 122 mmol) and the resulting solution was stirred for 10 min. Then, tert-butyldimethylsilyl chloride (6.76 g, 44.8 mmol) was added slowly and the reaction mixture was stirred at room temperature until disappearance of starting material by TLC (16 h). The reaction mixture was then diluted with ice-cold water (50 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were then washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography eluting with 25% EtOAc / heptane to give the product (I-36) (12.1 g, 77% yield).

[0162] (c) tert-Butyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (I-37) To a stirred solution of 1-(tert-butyl) 2-methyl(2R,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (12.0 g, 33.4 mmol) (I-36) in THF (120 mL) was added lithium borohydride (2M in THF) (41.7 mL, 2.5 equiv, 83.4 mmol) at 0 °C. The reaction mixture was then stirred at room temperature until disappearance of starting material was observed by TLC (16 h), then the reaction mixture was quenched by addition of saturated ammonium chloride solution and extracted with EtOAc (200 mL). The organic layer was then washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was then purified by silica gel chromatography eluting with 20-30% EtOAc / heptane to give the product (I-37) (11.1 g, 92% yield).

[0163] (d) tert-Butyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate (I-38) To a stirred solution of tert-butyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.00 g, 15.1 mmol) (I-37) in DMF (50.0 mL) was added sodium hydride (905 mg, 22.6 mmol) slowly at 0° C. and the reaction mixture was stirred for 30 min. Methyl iodide (4.28 g, 30.2 mmol) was then added dropwise and the reaction mixture was stirred at room temperature until disappearance of starting material was observed by TLC (2 h). The reaction mixture was then diluted with ice-cold water and extracted with EtOAc (3 times). The combined organic layers were then washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was then purified by silica gel chromatography eluting with 25% EtOAc / heptane to give the product (I-38) (4.1 g, 69% yield).

[0164] (e) tert-Butyl (2R,4R)-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (I-39) To a stirred solution of tert-butyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(methoxymethyl)pyrrolidine-1-carboxylate (4.00 g, 11.6 mmol) (I-38) in THF (40.0 mL) was added tetra-N-butylammonium fluoride (1 M in THF) (23.2 mL, 23.2 mmol) at 0° C. The reaction mixture was then stirred at room temperature until disappearance of starting material was observed by TLC (16 h). The reaction mixture was then diluted with cold water and extracted with EtOAc. The organic layer was then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography eluting with 25-30% EtOAc / Hexane to give the product (I-39) (2.6 g, 86% yield).

[0165] (f) tert-Butyl (R)-2-(methoxymethyl)-4-oxopyrrolidine-1-carboxylate (I-40) To a stirred solution of tert-butyl (2R,4R)-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (7.90 g, 34.2 mmol) (I-39) in dichloromethane (80.0 mL) was added Dess-Martin periodinane (29.0 g, 68.3 mmol) and the reaction mixture was stirred at room temperature until disappearance of starting material was observed by TLC (16 h). The reaction mixture was then filtered through a pad of Celite and rinsed with dichloromethane. The filtrate was then washed with ice-cold water, after which the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography eluting with 15% EtOAc / heptane to give the product (I-40) (6.6 g, 62% yield).

[0166] (g) tert-Butyl (R)-2-(methoxymethyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-41) To a stirred solution of tert-butyl (R)-2-(methoxymethyl)-4-oxopyrrolidine-1-carboxylate (6.50 g, 28.4 mmol) (I-40) in THF (70.0 mL) was added sodium bis(trimethylsilyl)amide (1 M in THF) (31.2 mL, 31.2 mmol) under nitrogen atmosphere at −78° C. and the reaction mixture was stirred for 30 min. Then, a solution of N-(5-chloropyridin-2-yl)-N-(methanesulfonyl)methanesulfonamide (12.3 g, 31.2 mmol) in THF (5.0 ml) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 30 min, then allowed to warm to room temperature and stirred until disappearance of starting material was observed by TLC (16 h). The reaction mixture was then quenched by addition of ice-cold water and extracted with EtOAc. The organic layer was then washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography eluting with 15% EtOAc / heptane to give the product (I-41) (5.8 g, 48% yield).

[0167] (h) tert-Butyl (R)-2-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-42) To a stirred solution of tert-butyl (R)-2-(methoxymethyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (5.80 g, 16.1 mmol) (I-41) in 1,4-dioxane (58.0 mL) was added bis(pinacolato)diboron (4.08 g, 16.1 mmol) and potassium acetate (3.15 g, 32.1 mmol). The reaction mixture was then purged with argon for 10 minutes, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (1.31 g, 1.61 mmol) was added. The reaction mixture was then stirred at 110° C. until judged complete by TLC and LCMS (4 h). The reaction mixture was then filtered through a pad of Celite, which was then rinsed with EtOAc. The filtrate was then concentrated under reduced pressure and the resulting crude product was purified by silica gel chromatography eluting with 5% EtOAc / heptane to give the product (I-42) (1.9 g, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ 6.35 (s, 1H), 4.53 (s, 1H), 4.10 (d, J = 15.2 Hz, 1H), 4.01 - 3.85 (m, 1H), 3.61 - 3.51 (m, 1H), 3.47 - 3.36 (m, 1H), 3.23 (d, J = 7.3 Hz, 3H), 1.41 (s, 9H), 1.22 (s, 12H).

[0168] Preparation of 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I-49) [ka]

[0169] (a) 2-Bromo-4-fluoro-5-methoxybenzaldehyde (I-44) To a stirred solution of 4-fluoro-3-methoxybenzaldehyde (100 g, 648 mmol) (I-43) in water (800 mL) was added KBr (231 g, 1946 mmol). The suspension was stirred at room temperature for 30 min, after which Br2 (66.9 mL, 1297 mmol) was added dropwise at room temperature. The resulting solution was stirred at room temperature for 1 h. TLC indicated complete consumption of starting material. The product precipitated from solution and was collected by filtration, washed with water (2×300 mL), and dried under reduced pressure to give the desired product as a pale yellow solid (135 g, 89% yield). 1 H NMR (400 MHz, chloroform-d) δ 10.24 (s, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 10.0 Hz, 1H), 3.93 (s, 3H).

[0170] (b) 1-(2-bromo-4-fluoro-5-methoxyphenyl)ethan-1-ol (I-45) To a solution of compound I-44 (90.0 g, 386 mmol) in dry THF (600 mL) was added 3.0 M MeMgCl (386 mL, 1158 mmol) dropwise at 0° C. The resulting reaction mixture was warmed to room temperature and stirred for 16 h. TLC indicated complete consumption of starting material. The reaction mixture was carefully quenched with saturated NH4Cl solution (800 mL) and further diluted with water (300 mL). The mixture was extracted with ethyl acetate (3×500 mL), dried over Na2SO4, and concentrated under reduced pressure to give the desired product as a colorless liquid (80 g, 83% yield). The reaction was used directly in the subsequent step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 10.8 Hz, 1H), 7.33 (d, J = 9.3 Hz, 1H), 5.50 (s, 1H), 4.88 (d, J = 6.5 Hz, 1H), 3.85 (s, 3H), 1.28 (d, J = 6.3 Hz, 3H).

[0171] (c) 1-Bromo-2-ethyl-5-fluoro-4-methoxybenzene (I-46) To a stirred solution of compound I-45 (72.0 g, 289 mmol) in DCM (800 mL) at 0 °C, Et3SiH (116 mL, 723 mmol) was added followed by TFA (178 mL, 2312 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. TLC indicated complete consumption of starting material. The reaction mixture was concentrated under reduced pressure and the crude was dissolved in EtOAc (400 mL) and washed with water (400 mL), saturated NaHCO3 solution (400 mL) and brine (400 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography (1-2% EtOAc in hexanes) to give the desired product (42.0 g, 65% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.25 (d, J = 10.9 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H), 2.70 (q, J = 7.6 Hz, 2H), 1.22 (q, J = 7.6 Hz, 3H).

[0172] (d) 4-Bromo-5-ethyl-2-fluorophenol (I-47) To a stirred solution of compound I-46 (42.0 g, 180 mmol) in DCM (150 mL) was added BBr3 (26.0 mL, 270.38 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was carefully quenched by dropwise addition of MeOH at 0° C. Then the reaction mixture was diluted with water (200 mL) and extracted with DCM (2×300 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product as a green liquid (30.0 g, 76% yield). It was used directly in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 7.25 (d, J = 10.1 Hz, 1H), 6.89 (d, J = 9.2 Hz, 1H), 5.15 (s, 1H), 2.65 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H).(m / z):[M+H]+ Calculated value for C8H9BrFO: 218.98; found value: 218.91.

[0173] (e) 1-(benzyloxy)-4-bromo-5-ethyl-2-fluorobenzene (I-48) To a solution of compound I-47 (22 g, 100.4 mmol) in ACN (200 mL) was added K2CO3 (27.7 g, 200.9 mmol) at room temperature followed by BnBr (13.9 mL, 120.5 mmol). The resulting reaction mixture was heated to 80 °C and stirred for 2 h. TLC indicated complete consumption of starting material. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (3-5% EtOAc in heptane) to give the desired product (20.0 g, 65% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.38 (m, 5H), 7.27 (d, J = 10.4 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.12 (s, 2H), 2.67 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H).

[0174] (f) 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I-49) To a solution of I-48 (15.0 g, 48.5 mmol) in dioxane (150 mL) was added bis(pinacolato)diboron (12.32 g, 48.5 mmol) and KOAc (14.3 g, 145.6 mmol). The reaction mixture was sparged with argon for 5 min, then PdCl2(dppf).DCM (3.9 g, 4.84 mmol) was added. The reaction mixture was heated to 110 °C and stirred under argon atmosphere for 16 h. TLC showed complete consumption of starting material. The reaction mixture was filtered through a celite pad and washed with ethyl acetate. The filtrate was then diluted with ethyl acetate (100 mL), washed with water (50 mL) and brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The crude material was then purified by silica gel column chromatography (3-5% EtOAc in heptane) to give the desired product as an off-white solid (12.0 g, 69% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.48 (d, J = 12.1 Hz, 1H), 7.45 (d, J = 7.3 Hz, 2H), 7.38 (t, J = 7.3 Hz, 2H), 7.35 - 7.28 (m, 1H), 6.82 (d, J = 7.9 Hz, 1H), 5.16 (s, 2H), 2.84 (q, J = 7.5 Hz, 2H), 1.32 (s, 12H), 1.14 (t, J = 7.5 Hz, 3H).

[0175] Preparation of 4-(3-(4-bromo-1H-imidazol-2-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (I-54) [ka]

[0176] (a) 3-(1-benzyl-1H-imidazol-2-yl)-6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-50) To a stirred solution of I-22 (2.0 g, 4.40 mmol) and I-49 (1.72 g, 4.84 mmol) in dioxane:H2O (16.0 mL:4.0 mL) was added Na2CO3 (932 mg, 8.80 mmol). The reaction mixture was sparged with argon for 15 min, and then PdCl2(dppf).DCM (360 mg, 0.44 mmol) was added to the reaction mixture. The reaction mixture was then heated to 100 °C and stirred under an argon atmosphere for 5 h. LCMS and TLC showed complete consumption of starting material. The reaction mixture was then filtered through a celite pad and the residue was washed with ethyl acetate. The filtrate was diluted with ethyl acetate (200 mL) and washed with cold water (200 mL) and brine (200 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure, and purified by silica gel column chromatography (11% EtOAc in heptane) to give the product as an off-white solid (2.0 g, 76% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.5 Hz, 1H), 7.55 - 7.48 (m, 3H), 7.44 (t, J = 7.4 Hz, 2H), 7.40 - 7.33 (m, 1H), 7.30 (d, J = 6.6 Hz, 2H), 7.26 (d, J = 5.4 Hz, 1H), 7.23 (d, J = 8.6 Hz, 4H), 7.18 - 7.09 (m, 2H), 5.90 (d, J = 15.4 Hz, 1H), 5.88 (s, 2H), 5.80 (d, J = 15.4 Hz, 1H), 5.26 (s, 2H), 3.84 (s, 1H), 3.61 (t, J = 10.6 Hz, 1H), 3.31 (d, J = 9.4 Hz, 1H), 2.42 (d, J = 7.4 Hz, 2H), 2.36 (s, 1H), 2.02 (s, 1H), 1.69 (s, 1H), 1.53 (s, 1H), 0.99 (t, J = 7.5 Hz, 3H).(m / z):[M+H] + C 37 H 35 Calculated value of F2N4O2: 605.27, measured value: 605.94.

[0177] (b) 5-ethyl-2-fluoro-4-(7-fluoro-3-(1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)phenol (I-51) To a stirred solution of I-50 (2.0 g, 3.31 mmol) in IPA:THF (15 mL:5 mL) was added 20% Pd(OH)2 / C (1.5 g). The reaction mixture was subjected to hydrogenation using a H2 balloon and stirred at room temperature for 16 h. TLC showed complete consumption of starting material. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to give the desired product as an off-white solid (1.4 g, 99% yield). The product was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 8.3 Hz, 1H), 7.21 (s, 1H), 7.11 (dd, J = 8.2, 5.9 Hz, 1H), 7.02 (d, J = 11.8 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 5.89 (d, J = 9.4 Hz, 1H), 3.95 (d, J = 11.3 Hz, 1H), 3.66 (dt, J = 11.5, 6.5 Hz, 1H), 3.38 (q, J = 7.0 Hz, 1H), 2.56 (d, J = 11.7 Hz, 1H), 2.36 (q, J = (m / z):[M+H] + C 23 H 23 Calculated F2N4O2 value: 425.18, measured value: 425.10.

[0178] (c) 6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1H-indazole (I-52) To a stirred solution of I-51 (1.4 g, 3.30 mmol) in DMF (20.0 mL) was added NaH (528 mg, 13.2 mmol) at 0° C. The reaction mixture was then stirred at 0° C. for 30 min, and then SEMCl (1.76 mL, 9.90 mmol) was added dropwise. The reaction mixture was then warmed to room temperature and stirred for 2 h. TLC indicated complete consumption of starting material. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (200 mL), dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (10% EtOAc in heptane) to give the desired product as a clear amorphous solid (1.5 g, 66% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 1.3 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.22 - 7.10 (m, 3H), 5.93 (t, J = 8.7 Hz, 4H), 5.36 (s, 2H), 3.92 (d, J = 11.3 Hz, 1H), 3.79 (t, J = 8.0 Hz, 2H), 3.66 (s, 1H), 3.52 (t, J = 8.0 Hz, 2H), 3.28 (d, J = 7.5 Hz, 2H), 2.42 (d, J = 7.8 Hz, 2H), 2.15 (d, J = 14.1 Hz, 1H), 2.08 (d, J = 13.2 Hz, 1H), 1.77 (s, 1H), 1.58 (s, 2H), 0.99 (t, J = 7.5 Hz, 3H), 0.93 (t, J = 8.0 Hz, 2H), 0.80 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H), -0.14 (s, 9H).(m / z):[M+H]+ C 35 H 52 Calculated value of F2N4O4Si2: 685.34, measured value: 685.18.

[0179] (d) 3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (I-53) A stirred solution of I-52 (1.5 g, 2.19 mmol) in DCM (60 mL) was cooled to 0° C. In a separate vial, recrystallized NBS (390 mg, 2.19 mmol) was dissolved in DCM (15.0 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at 0° C. for 5 min. TLC showed conversion of starting material. The reaction mixture was quenched with water and extracted with DCM (200 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (8.5% EtOAc in heptane) to give the desired product as a clear amorphous solid (1.3 g, 77% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 10.5 Hz, 2H), 5.98 (s, 1H), 5.93 (d, J = 9.8 Hz, 2H), 5.36 (s, 2H), 3.93 (d, J = 11.3 Hz, 1H), 3.79 (t, J = 8.0 Hz, 2H), 3.66 (s, 1H), 3.52 (t, J = 8.0 Hz, 2H), 3.30 (d, J = 7.5 Hz, 2H), 2.41 (d, J = 7.9 Hz, 2H), 2.15 (d, J = 12.9 Hz, 1H), 2.06 (s, 1H), 1.78 (s, 1H), 1.58 (s, 2H), 0.99 (t, J = 7.5 Hz, 3H), 0.93 (t, J = 8.0 Hz, 2H), 0.78 (t, J = 8.1 Hz, 2H), 0.00 (s, 9H), -0.17 (s, 9H).(m / z):[M+H] + C 35 H 50 Calculated value for BrF2N4O4Si2: 765.25; measured value: 765.88.

[0180] (e) 4-(3-(4-bromo-1H-imidazol-2-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (I-54) To a stirred solution of I-53 (1.3 g, 1.70 mmol) in THF (10 mL) was added 1.0 M TBAF (13 mL) at room temperature. The reaction mixture was heated to 80° C. and stirred for 16 h. TLC showed complete consumption of starting material. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (18% EtOAc in heptane) to give the desired product as an off-white solid (625 mg, 72% yield). 11H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.98 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.15 (dd, J = 8.3, 6.0 Hz, 1H), 7.06 (d, J = 11.6 Hz, 1H), 6.96 (dd, J = 9.1, 2.2 Hz, 1H), 5.90 (dd, J = 9.9, 2.3 Hz, 1H), 3.95 (d, J = 11.6 Hz, 1H), 3.71 - 3.60 (m, 1H), 3.30 (d, J = 7.5 Hz, 2H), 2.37 (q, J = 7.8 Hz, 2H), 2.11 (d, J = 12.3 Hz, 2H), 1.74 (s, 1H), 1.60 - 1.54 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H).(m / z):[M+H] + C 23 H 22 Calculated value for BrF2N4O2: 503.09, measured value: 502.94.

[0181] General procedure for the preparation of the compound Suzuki coupling reaction

Chemical formula

[0182] Starting materials 4-(3-(4-bromo-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-3-ethylphenol (I-17), 4-(3-(4-bromo-1H-imidazol-2-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-3-ethylphenol (I-2 7), or 4-(3-(4-bromo-1H-imidazol-2-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (I-54) (1 eq.) and the boronic acid or ester (1.5 eq.) were dissolved in enough 1,4-dioxane to achieve a concentration of I-17 / I-27 of about 0.15 mmol. Sodium carbonate was then dissolved in water (a volume equal to about 1 / 3 the volume of 1,4-dioxane used) and the resulting solution was added to the 1,4-dioxane solution. The reaction flask was then purged with nitrogen. Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (0.05 equiv.) was added and the reaction mixture was stirred and heated at 110 °C until the reaction was judged complete by LCMS (8-24 h). The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate solution, and the dichloromethane layer was collected, dried over sodium sulfate, and then concentrated by rotary evaporation. The resulting crude product was then purified by silica gel chromatography (gradient of 0-10% methanol / dichloromethane). Deprotection reaction [ka]

[0183] Method A The product of the Suzuki reaction was dissolved in a volume of methanol sufficient to achieve a solution concentration of 0.1-0.2 mmol, then concentrated HCl equal to 1 / 2 the volume of methanol used was added, and the reaction mixture was stirred and heated at 50 °C until judged complete by LCMS (4-24 h). For small-scale reactions (solution volume <5 mL), the reaction mixture was then partially concentrated to remove most of the methanol, and the resulting solution was diluted with a mixture of acetonitrile / water and purified by reverse-phase chromatography (5-70% acetonitrile / water gradient, with 0.05% TFA). For larger-scale reactions, the reaction mixture was added dropwise to aqueous ammonia (concentrated ammonia solution diluted 1:5 in water) to precipitate the product, which was then collected by filtration. The resulting solid was then purified by reverse-phase chromatography (5-70% acetonitrile / water gradient, with 0.05% TFA).

[0184] Method B The product of the Suzuki reaction was dissolved in a mixture of 4M HCl in 1,4-dioxane (30-40 equiv.) and water (20% of the volume of the HCl / dioxane solution), then the reaction mixture was stirred and heated at 60° C. until judged complete by LCMS (8-48 h). The reaction mixture was then frozen and lyophilized, and the resulting solid was purified by reverse phase chromatography (0-70% acetonitrile / water gradient with 0.05% TFA).

[0185] Method C The product of the Suzuki reaction was dissolved in TFA (30-50 equiv.) and the reaction mixture was stirred at room temperature until judged complete by LCMS (1-24 h). The reaction mixture was then concentrated by rotary evaporation and the crude product was purified by preparative HPLC (5-70% acetonitrile / water gradient with 0.05% TFA).

[0186] Example 1 4-(3-(4-(2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazol-2-yl)-7-fluoro-1H-indazol-6-yl)-3-ethylphenol (1) [ka]

[0187] Following the general procedure, 1.20 mmol of I-27 was used, tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate was used as the boronate ester, and method B was used for deprotection to give the TFA salt of the title compound (341 mg, 57% yield). (m / z): [M+H]+ C 22 H 20 Calculated FN5O value: 390.17, measured value: 390.2. 1 H NMR (601 MHz, methanol-d4) δ 7.94 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.05 (t, J = 6.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.72 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.38 (s, 1H), 4.39 (s, 2H), 4.22 (s, 2H), 2.38 (q, J = 7.6 Hz, 2H), 0.95 (t, J = 7.5 Hz, 3H).

[0188] Example 2 3-Ethyl-4-(7-fluoro-3-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (2) [ka]

[0189] Following the general procedure, 4.12 mmol of I-27 was used, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used as the boronic ester, and method A was used for deprotection to give the TFA salt of the title compound (1.39 g, 62% yield). (m / z): [M+H]+ C 23 H 22 Calculated FN5O value: 404.18, measured value: 404.1. 1 H NMR (601 MHz, methanol-d4) δ 7.89 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 7.08 (dd, J = 8.3, 6.1 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.71 (s, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.45 (s, 1H), 3.85 (s, 2H), 3.42 (t, J = 6.1 Hz, 2H), 2.76 (s, 2H), 2.38 (q, J = 7.5 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H).

[0190] Example 3 3-Ethyl-4-(3-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (3) [ka]

[0191] Following the general procedure, 4.28 mmol of I-17 was used, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used as the boronate ester, and method A was used for deprotection to give the TFA salt of the title compound (1.17 g, 55% yield). (m / z): [M+H]+ C 23 H 23 Calculated N5O value: 386.19, measured value: 386.1. 1H NMR (601 MHz, methanol-d4) δ 8.06 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.43 (s, 1H), 7.20 (dd, J = 8.4, 1.4 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.69 (s, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.47 (s, 1H), 3.86 (s, 2H), 3.43 (t, J = 6.1 Hz, 2H), 2.76 (s, 2H), 2.47 (q, J = 7.6 Hz, 2H), 0.97 (t, J = 7.5 Hz, 3H).

[0192] Example 4 3-Ethyl-4-(3-(4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (4) [ka]

[0193] Following the general procedure, 0.096 mmol of I-17 was used, tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used as the boronate ester, and method C was used for deprotection to give the TFA salt of the title compound (10 mg, 40% yield). (m / z): [M+H]+ C 23 H 23 Calculated N5O value: 386.19, measured value: 386.2.

[0194] Example 5 4-(3-(4-(2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-3-ethylphenol (5) [ka]

[0195] Following the general procedure, 0.214 mmol of I-17 was used, tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate was used as the boronate ester, and method B was used for deprotection to give the TFA salt of the title compound (29 mg, 28% yield). (m / z): [M+H]+ C 22 H 21 Calculated N5O value: 372.18, measured value: 372.2. 1 H NMR (601 MHz, methanol-d4) δ 8.11 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.71 (s, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.51 (s, 1H), 4.43 (s, 2H), 4.27 (s, 2H), 2.48 (q, J = 7.5 Hz, 2H), 0.98 (t, J = 7.5 Hz, 3H).

[0196] Example 6 3-Ethyl-4-(7-fluoro-3-(4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (6) [ka]

[0197] Following the general procedure, 2.06 mmol of I-27 was used, tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used as the boronic ester, and method B was used for deprotection to give the TFA salt of the title compound (0.65 g, 61% yield). (m / z): [M+H]+ C 23 H 22 Calculated FN5O value: 404.18, measured value: 404.1. 1H NMR (601 MHz, methanol-d4) δ 7.91 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.06 (dd, J = 8.2, 6.1 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.71 (s, 1H), 6.62 (d, J = 5.8 Hz, 2H), 4.04 (s, 2H), 3.34 (t, J = 6.2 Hz, 2H), 2.57 (s, 2H), 2.38 (q, J = 7.6 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H).

[0198] Example 7 4-(3-(4-(3-oxa-9-azabicyclo[3.3.1]non-6-en-7-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-3-ethylphenol (7) [ka]

[0199] Following the general procedure, 0.214 mmol of I-17 was used, 7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-oxa-9-aza-bicyclo[3.3.1]non-6-ene-9-carboxylic acid tert-butyl ester was used as the boronic ester, and method B was used for deprotection to give the TFA salt of the title compound (14 mg, 12% yield). (m / z): [M+H]+ C 25 H 25 Calculated N5O2 value: 428.20, measured value: 428.0.

[0200] Example 8 (R)-3-Ethyl-4-(7-fluoro-3-(4-(5-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (8) [ka]

[0201] Following the general procedure, 1.24 mmol of I-27 was used, I-33 was used as the boronic ester, and method B was used for deprotection to give the TFA salt of the title compound (306 mg, 42% yield). (m / z): [M+H]+ C 23 H 22 Calculated value of FN5O2: 420.18, measured value: 420.1.

[0202] Example 9 (R)-3-Ethyl-4-(7-fluoro-3-(4-(5-(methoxymethyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (9) [ka]

[0203] Following the general procedure, 0.103 mmol of I-27 was used, I-42 was used as the boronic ester, and method B was used for deprotection to give the TFA salt of the title compound (29 mg, 51% yield). (m / z): [M+H]+ C 24 H 24 Calculated FN5O2 value: 434.19, measured value: 434.2.

[0204] Example 10 3-Ethyl-4-(7-fluoro-3-(4-(1-(3-hydroxycyclobutyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (10) [ka]

[0205] 3-Ethyl-4-(7-fluoro-3-(4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol, TFA (20 mg, 0.039 mmol) and 3-hydroxycyclobutanone (7 mg, 0.077 mmol) were dissolved in methanol (1 mL). Sodium cyanoborohydride (12 mg, 0.193 mmol) was then added and the reaction mixture was stirred at room temperature until judged complete by LCMS (24 h). The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-75% acetonitrile / water gradient with 0.05% TFA) to give the TFA salt of the title compound (17.3 mg, 75% yield). (m / z): [M+H]+ C 27 H 28 Calculated FN5O2 value: 474.23, measured value: 474.1.

[0206] Example 11 4-(3-(4-(1-((1H-pyrazol-4-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-7-fluoro-1H-indazol-6-yl)-3-ethylphenol (11) [ka]

[0207] 3-Ethyl-4-(7-fluoro-3-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol, TFA (20 mg, 0.039 mmol) and 1H-pyrazole-4-carboxaldehyde (7 mg, 0.077 mmol) were dissolved in methanol (1 mL). Sodium cyanoborohydride (12.14 mg, 0.193 mmol) was then added and the reaction mixture was stirred at room temperature until judged complete by LCMS (24 h). The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-75% acetonitrile / water gradient with 0.05% TFA) to give the TFA salt of the title compound (15.1 mg, 65% yield). (m / z): [M+H]+ C 27 H 26 Calculated value for FN7O: 484.22, measured value: 484.1.

[0208] Example 12 2-(4-(2-(6-(2-ethyl-4-hydroxyphenyl)-7-fluoro-1H-indazol-3-yl)-1H-imidazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)-N-methylacetamide (12) [ka]

[0209] 3-Ethyl-4-(7-fluoro-3-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol, TFA (20 mg, 0.039 mmol), 2-bromo-N-methyl-acetamide (7 mg, 0.046 mmol), and N,N-diisopropylethylamine (0.027 ml, 0.155 mmol) were dissolved in DMF (1 mL). The reaction mixture was then stirred at 50° C. until judged complete by LCMS (24 h). The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-75% acetonitrile / water gradient with 0.05% TFA) to give the TFA salt of the title compound (8.8 mg, 38% yield). (m / z): [M+H]+ C 26 H 27 Calculated FN6O2 value: 475.22, measured value: 475.1.

[0210] Example 13 3-Ethyl-4-(7-fluoro-3-(4-(1-(1-hydroxypropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (13) [ka]

[0211] 3-Ethyl-4-(7-fluoro-3-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol, TFA (30 mg, 0.058 mmol) and hydroxyacetone (21 mg, 0.290 mmol) were dissolved in methanol (1.0 ml) then sodium cyanoborohydride (22 mg, 0.348 mmol) was added and the reaction mixture was stirred at 50° C. until judged complete by LCMS (24 h). The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-70% acetonitrile / water gradient with 0.05% TFA) to give the TFA salt of the title compound (28.4 mg, 85% yield). (m / z): [M+H]+ C 26 H 28 Calculated FN5O2 value: 462.23, measured value: 462.1.

[0212] Example 14 3-Ethyl-4-(7-fluoro-3-(4-(1-(3-hydroxypropyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (14) [ka]

[0213] 3-Ethyl-4-(7-fluoro-3-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol, TFA (30.0 mg, 0.058 mmol) and 3-(tert-butyldimethylsilyloxy)propanol (22 mg, 0.116 mmol) were dissolved in methanol (1.0 ml) and then sodium cyanoborohydride (18 mg, 0.290 mmol) was added and the reaction mixture was stirred at room temperature until complete (24 hours) as judged by LCMS. The reaction mixture was then concentrated and the silyl protected intermediate was dissolved in 3 mL of acetonitrile:water (1:1). 0.5 mL of TFA was then added and the solution was left at room temperature until complete removal of the silyl group was judged by LCMS (30 minutes). The solution was then filtered and purified by preparative HPLC (5-70% acetonitrile / water gradient with 0.05% TFA) to give the TFA salt of the title compound (17.1 mg, 51% yield). (m / z): [M+H]+ C 26 H 28 Calculated FN5O2 value: 462.23, measured value: 462.2.

[0214] Example 15 3-Ethyl-4-(3-(4-(1-(1-methylazetidin-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (15) [ka]

[0215] 3-Ethyl-4-(3-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol, TFA (20 mg, 0.040 mmol) and 1-methylazetidin-3-one hydrochloride (15 mg, 0.120 mmol) were dissolved in methanol (1 ml) then sodium cyanoborohydride (13 mg, 0.200 mmol) was added and the reaction mixture was stirred at 50° C. until complete (24 h) by LCMS. The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-70% acetonitrile / water gradient with 0.05% TFA) to give the TFA salt of the title compound (14.1 mg, 52% yield). (m / z): [M+H]+ C 27 H 30 Calculated N6O value: 455.25, measured value: 455.2.

[0216] Example 16 (S)-6-(2-ethyl-4-hydroxyphenyl)-7-fluoro-3-(4-(1-prolyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazole (16) [ka]

[0217] 3-Ethyl-4-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol, TFA (20 mg, 0.033 mmol), N-Boc-L-proline (11 mg, 0.050 mmol), and N,N-diisopropylethylamine (17 μL, 0.10 mmol) were dissolved in DMF (1 mL). HATU (19 mg, 0.050 mmol) was then added and the reaction mixture was stirred at room temperature until judged complete by LCMS (24 h). Hydrazine (5 μl, 0.166 mmol) was then added to cleave the undesired by-product and the reaction mixture was concentrated. The residue was then dissolved in TFA (1 mL) and stirred at room temperature until LCMS indicated complete removal of the Boc protecting group (30 min). The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-70% acetonitrile / water gradient with 0.05% TFA) to give the TFA salt of the title compound (12.9 mg, 63% yield). (m / z): [M+H]+ C 28 H 29 Calculated value of FN6O2: 501.24, measured value: 501.3.

[0218] (Example 17) (R)-3-Ethyl-4-(3-(4-(1-(morpholin-3-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (17) [ka]

[0219] 3-Ethyl-4-(3-(4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol, TFA (20 mg, 0.040 mmol) and (S)-N-Boc-3-morpholinecarbaldehyde (13 mg, 0.060 mmol) were dissolved in methanol (1.0 ml) then sodium cyanoborohydride (10 mg, 0.160 mmol) was added and the reaction mixture was stirred at room temperature until complete by LCMS (48 h). The reaction mixture was then concentrated and the resulting residue was dissolved in TFA (1 mL) and stirred at room temperature until complete removal of the Boc group was observed by LCMS (10 min). The reaction mixture was then concentrated and the crude product was purified by preparative HPLC (5-70% acetonitrile / water gradient with 0.05% TFA) to give the TFA salt of the title compound (7.8 mg, 27% yield). (m / z): [M+H]+ C 28 H 32 Calculated N6O2 value: 485.26, measured value: 485.2.

[0220] (Example 18) 4-(3-(4-(2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazol-2-yl)-7-fluoro-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (18) [ka]

[0221] 4-(3-(4-Bromo-1H-imidazol-2-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (200 mg, 0.397 mmol) (I-54) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (176 mg, 0.596 mmol) were dissolved in dioxane (4.0 ml) followed by the addition of sodium carbonate (126 mg, 1.192 mmol) in water (2.0 ml). The reaction vial was purged with nitrogen, then methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.10 mg, 0.020 mmol) was added and the reaction mixture was stirred at 110° C. until complete by LCMS (16 h). The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate solution, after which the dichloromethane layer was dried over sodium sulfate and concentrated. The crude product was then purified by silica gel chromatography (0-10% methanol / dichloromethane gradient) to give the protected intermediate tert-butyl 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-imidazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (183 mg, 78% yield). This intermediate was then deprotected using Method B from the general procedure to give the TFA salt of the title compound (107 mg, 54% yield). (m / z): [M+H]+ C 22 H 19 The calculated value of F2N5O was 408.16, and the measured value was 408.2.

[0222] Using the procedures described in the above examples or analogous synthetic methods and appropriate reactants, the compounds in Table 4 below were prepared. [Table 4-1]

Table 4-2

Table 4-3

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

Table 4-9

Table 4-10

Table 4-11

Table 4-12

Table 4-13

Table 4-14

Table 4-15

Table 4-16

Table 4-17

Table 4-18

Table 4-19

Table 4-20

Table 4-21

Table 4-22

Table 4-23

Table 4-24

Table 4-25

Table 4-26

Table 4-27

Table 4-28

Table 4-29

Table 4-30

Table 4-31

Table 4-32

Table 4-33

Table 4-34

Table 4-35

Table 4-36

Table 4-37

Table 4-38

Table 4-39

Table 4-40

Table 4-41

Table 4-42

Table 4-43

Table 4-44

Table 4-45

Table 4-46

Table 4-47

Table 4-48

Table 4-49

Table 4-50

Table 4-51

Table 4-52

Table 4-53

Table 4-54

Table 4-55

Table 4-56

Table 4-57

Table 4-58

Table 4-59

Table 4-60

Table 4-61

Table 4-62

Table 4-63

Table 4-64

Table 4-65

Table 4-66

Table 4-67

Table 4-68

Table 4-69

[0223] Biological assays

[0224] The compounds of the present invention and disclosure have been characterized in one or more of the following biological assays. Assay 1: Biochemical JAK kinase assay

[0225] A panel of four LanthaScreen JAK biochemical assays (JAK1, 2, 3 and Tyk2) were included in standard kinase reaction buffer (50 mM HEPES, pH 7.5, 0.01% Brij®-35, 10 mM MgCl2 and 1 mM EGTA). Recombinant GST-tagged JAK enzymes and GFP-tagged STAT1 peptide substrates were obtained from Life Technologies.

[0226] Serially diluted compounds were pre-incubated with each of the four JAK enzymes and substrates in a white 384-well microplate (Corning) at ambient temperature for 1 hour. ATP was then added to initiate the kinase reaction in a total volume of 10 μL containing 1% DMSO. The final enzyme concentrations for JAK1, 2, 3 and Tyk2 were 4.2 nM, 0.1 nM, 1 nM and 0.25 nM, respectively; the corresponding Km ATP concentrations used were 25 μM, 3 μM, 1.6 μM and 10 μM; the substrate concentration was 200 nM for all four assays. The kinase reaction was allowed to proceed for 1 hour at ambient temperature, after which a 10 μL preparation of EDTA (final concentration 10 mM) and Tb-anti-pSTAT1 (pTyr701) antibody (Life Technologies, final concentration 2 nM) in TR-FRET dilution buffer (Life Technologies) was added. The plate was incubated for 1 hour at ambient temperature before being read on an EnVision reader (Perkin Elmer). Emission ratio signals (520 nm / 495 nm) were recorded and used to calculate percent inhibition values ​​based on DMSO and background controls.

[0227] For dose-response analysis, percent inhibition data were plotted versus compound concentration and IC values ​​were calculated from a four-parameter robust fit model using Prism software (GraphPad Software). 50 The results were shown in pIC 50 (I C 50 pK is expressed as the negative logarithm of pK i (the negative logarithm of the dissociation constant Ki).

[0228] Lower K in four JAK assays i value or higher pK i Test compounds having a value greater than or equal to 100% of the JAK activity exhibit greater inhibition of JAK activity.

[0229] Assay 2: Cellular JAKI potency assay

[0230] JAKI cell potency assays were performed by measuring inhibition of interleukin-13 (IL-13, R&D Systems)-induced STAT6 phosphorylation in BEAS-2B human lung epithelial cells (ATCC). BEAS-2B cells were grown in 50% DMEM / 50% F-12 medium (Life Technologies) supplemented with 10% FBS (Hyclone), 100 U / mL penicillin, 100 μg / mL streptomycin (Life Technologies), and 2 mM GlutaMAX (Life Technologies) at 37°C in a 5% CO2 humidified incubator. On day 1 of the assay, cells were seeded at a density of 7,500 cells / well in white poly-D-lysine-coated 384-well plates (Corning) in 25 μL of medium and allowed to adhere overnight in the incubator. On the second day of the assay, the medium was removed and replaced with 12 μL of assay buffer (Hank's Balanced Salt Solution / HBSS, 25 mM HEPES, and 1 mg / ml bovine serum albumin / BSA) containing a dose response of the test compound. Compounds were serially diluted in DMSO and then diluted another 1000-fold in medium to a final DMSO concentration of 0.1%. Cells were incubated with the test compound for 1 hour at 37° C. and then stimulated by adding 12 μl of pre-warmed IL-13 (80 ng / mL in assay buffer). After 30 minutes of incubation at 37° C., the assay buffer (containing the compound and IL-13) was removed and replaced with 10 μL of cell lysis buffer (25 mM HEPES, 0.1% SDS, 1% NP-40, 5 mM MgCl2, 1.3 mM EDTA, 1 mM EGTA, supplemented with Complete Ultra Mini Protease Inhibitor and PhosSTOP from Roche Diagnostics). Plates were shaken for 30 minutes at ambient temperature before adding detection reagent. Levels of pSTAT6 were measured using the AlphaLISA SureFire Ultra pSTAT6 (Tyr641) Assay Kit from PerkinElmer. For dose-response analysis, percent inhibition data was plotted against compound concentration and IC values ​​were calculated from a 4-parameter robust fit model using Graphpad Prism software. 50The results were expressed as IC 50 Negative logarithm of the pIC value 50 It is expressed as:

[0231] A lower IC in this assay 50 value or higher pIC 50 Test compounds having a value exhibiting increased inhibition of IL-13-induced STAT6 phosphorylation.

[0232] In vitro assay results

[0233] Compounds were tested in the BEAS-2B cell potency assay and in at least two of the four JAK enzyme assays described above: JAK1, JAK2, JAK3, and TYK2.

[0234] In the table below, for JAK1, JAK2, JAK3, and TYK2 enzyme assays, A is the pK i Value ≧ 10(K i ≦0.1 nM), and B is a pK of 9 (included) to 10 i Values ​​(K range from 1 nM to 0.1 nM) i ) and C is a pK of 8 (included) to 9 i Values ​​(K from 10 nM to 1 nM) i ) and D is a pK of 7 (included) to 8 i Values ​​(K from 100 nM to 10 nM) i ), where E is a pK of 7 or less. i value (100 nM or higher K i In the BEAS2B potency assay, A represents a pIC of 8 (inclusive) to 8.5 50 A represents a pIC value between 7.5 (inclusive) and 8. 50 represents a pIC value between 7 (inclusive) and 7.5 50 D represents a pIC value between 6.5 (included) and 7 50 represents a pIC value of 6.0-6.5. 50 The values ​​shown are those for which no test was performed. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

[0235] Assay 3: Murine (Mouse) model of IL-13-induced pSTAT6 induction in lung tissue

[0236] IL-13 then binds to cell surface receptors that phosphorylate STAT6 and activate members of the Janus family of kinases (JAK), which then activate further transcriptional pathways. In the model described, a dose of IL-13 was delivered locally into the lungs of mice to induce phosphorylation of STAT6 (pSTAT6), which was then measured as an endpoint.

[0237] The assay used adult balb / c mice obtained from Harlan. On the day of the study, animals were lightly anesthetized with isoflurane and administered either vehicle or test compound (0.5 mg / mL, total volume of 50 μL over several breaths) by oral aspiration.

[0238] After dosing, animals were placed on their side and monitored for complete recovery from anesthesia before being returned to their home cage. Eight hours later, animals were briefly anesthetized again and challenged with either vehicle or IL-13 (total dose delivered 0.03 μg, total volume 50 μL) by oral aspiration, then monitored for recovery from anesthesia and returned to their home cage. One hour after vehicle or IL-13 administration, lungs were collected and analyzed for total drug concentration for both pSTAT6 detection using AlphaLISA Immunoassay (PerkinElmer).

[0239] Selected compounds of the present disclosure were tested in this assay. Activity in this model is demonstrated by a reduction in the level of pSTAT6 present in the lungs of animals treated at 9 hours compared to vehicle-treated, IL-13-loaded control animals. In both experiments, the difference between vehicle-treated, IL-13-loaded control animals and vehicle-treated, vehicle-loaded control animals defined 0% and 100% inhibitory effect, respectively. Exemplary compounds were tested in this assay and showed inhibition of STAT6 phosphorylation 9 hours after IL-13 loading, as described below.

[0240] In the table below, A represents 80% to 100% inhibition, B represents 60% to 80% inhibition, and C represents 40% to 60% inhibition. [Table 2]

[0241] Assay 4: Pharmacokinetics of test compounds in plasma and lungs in mice following oral inhalation administration

[0242] The plasma and lung concentrations of the test compound were quantified, and the pharmacokinetic parameters were calculated as follows. Male CD1 mice from Charles River Laboratories were used in the pharmacokinetic study. Test compounds were individually formulated in 20% propylene glycol in citrate buffer (pH 4) at a concentration of 0.2 mg / mL. Animals were anesthetized using isoflurane, and then test compounds were administered in two increments of 25 μL, introduced into the trachea of ​​each mouse by oral aspiration using a graduated pipette. Blood samples were collected as terminal collections by cardiac puncture at 0.167, 1, 4, 8, and 24 hours after administration. After CO2 inhalation, direct cardiac puncture was performed, avoiding lung puncture, and blood was immediately transferred to K2EDTA tubes and placed on ice. Blood samples were centrifuged (Eppendorf centrifuge, 5804R) at approximately 12,000 rpm for 4 minutes at 4°C to collect plasma. Intact lungs were also excised from these mice using the same time points (0.167, 1, 4, 8, and 24 hours). Lungs were washed with sterile water to remove any blood residue, patted dry, weighed, and homogenized in 0.1% formic acid in water at a dilution of 1:3 (lung:water, weight / volume). Plasma and lung test compound concentrations were determined by LC-MS / MS analysis against analytical standards constructed in a standard curve in the test matrix. Pharmacokinetic parameters of the test compounds were determined by non-compartmental analysis. For concentrations below the limit of quantification, zero was used to calculate the mean. Mean values ​​were not reported if more than 50% of the samples at a time point were below the limit of quantification or more than 50% of the calculated pharmacokinetic parameters were not reportable. Area under the concentration-time curve (AUC) extrapolated to infinite time(0-inf) ) was calculated as follows: AUC (0-inf) =AUC (0-t) +C last / k, where AUC (0-t) is the area under the concentration-time curve from administration to the last measurable concentration calculated by the linear trapezoidal rule, and C last is the last measurable concentration, and k is the first-order rate constant associated with the terminal elimination phase, estimated by linear regression of time versus log concentration. The lung to plasma AUC ratio was defined as the lung AUC (0-inf) Plasma AUC (unit: μg·h / g) (0-inf) The ratio was determined to the total protein concentration (unit: μg·h / mL).

[0243] In the table below, plasma AUC (0-24) In the above, A represents a value less than 0.5, B represents a value between 0.5 and 1, and C represents a value between 1 and 1.5. Lung tissue AUC (0-24) In the above, A represents a value between 100 and 200, B represents a value between 50 and 100, and C represents a value between 9 and 50. In the ratio of lung exposure to plasma exposure, A represents a ratio between 300 and 410, B represents a ratio between 200 and 300, C represents a ratio between 100 and 200, D represents a ratio between 50 and 100, and E represents a ratio between 30 and 50. [Table 3-1] [Table 3-2]

[0244] Although the present invention has been described with reference to specific aspects or embodiments thereof, it will be understood by those skilled in the art that various modifications may be made and equivalents may be substituted without departing from the true spirit and scope of the invention.Furthermore, to the extent permitted by applicable patent laws and regulations, all publications, patents, and patent applications cited herein are incorporated by reference in their entirety to the same extent as if each document was individually incorporated by reference herein.

Claims

1. A compound of formula (I): 【Chemical 47】 or a pharmaceutically acceptable salt thereof [wherein, W is H, -C １～６ alkyl or halogen, X is H or F, Y is H, -CH ３ , or F, and Z is -CH ２ CH ３ , -CF ２ CH ３ , or -CH ２ CF ３ and A has a double bond and is selected from the group consisting of -C １～６ alkyl, -COR １ -, -SO ２ R １ -, -CO ２ R ２ -, -CONR ２ R ３ -, -SO ２ NR ２ R ３ optionally substituted with 1 to 8 substituents independently selected from the group consisting of aryl, heteroaryl, 3- to 7-membered cycloalkyl groups, and 4- to 7-membered heterocyclic groups, and is a 4- to 7-membered monocyclic heterocyclic group The foregoing -C １～６ Alkyl is -C １～６ alkyl, -NR ２ R ３ , -CN, -CO ２ R ２ , -CONR ２ R ３ , -OH, -SO ２ NR ２ R ３ , -SO ２ -C １～６ alkyl, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -OC(O)NR ２ R ３ , -NR ２ C(O)-R １ , -NR ２ C(O) ２ R ３ , -NR ２ -C(O)NR ３ R ４ , -OCO ２ R ３ , -NR ２ SO ２ -C １～６ alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl group, and 4- to 7-membered heterocyclic group, independently selected from the group consisting of 1 to 5 substituents optionally substituted, wherein the 3- to 7-membered cycloalkyl group and the 4- to 7-membered heterocyclic group are oxo, -C １～６ alkyl, -CN, -CO ２ R ５ , -CONR ５ R ６ , -OH, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR ５ R ６ , -OC(O)NR ５ R ６ , -NR ５ C(O)-C １～６ alkyl, -NR ５ C(O) ２ R ６ , -NR ５ -C(O)NR ６ R ７ , -C １～６ Alkyl-OR ５ 、-C １～６ Alkyl-NR ５ R ６ 、and -C １～６ Alkyl-CO ２ R ５ optionally substituted with 1 to 5 substituents independently selected from the group consisting of, said aryl and heteroaryl being halogen, -CN, -CO ２ R ８ 、-CONR ８ R ９ 、-OH, -SH, -C １～６ Alkyl, -O-C １～６ Alkyl, -S-C １～６ Alkyl, -NR ８ R ９ 、-OC(O)NR ８ R ９ 、-OCO ２ R ８ 、-NR ８ C(O)-C １～６ Alkyl, -NR ８ C(O) ２ R ９ 、-NR ８ -C(O)NR ９ R １０ 、-C １～６ Alkyl-OR ８ 、-C １～６ Alkyl-NR ８ R ９ 、and -C １～６ Alkyl-CO ２ R ８ optionally substituted with 1 to 5 substituents independently selected from the group consisting of, A is a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group which may be optionally condensed or bridged, Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group is optionally substituted with 1 to 5 substituents independently selected from the group consisting of spiro 3- to 7-membered cycloalkyl groups, spiro 4- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, 4- to 7-membered heterocyclic groups, -C １～６ alkyl, -CF ３ , oxo, -CN, -CO ２ R １１ , -CONR １１ R １２ , -OH, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR １１ R １２ , -OC(O)NR １１ R １２ , -NR １１ C(O)-C １～６ alkyl, -NR １１ C(O) ２ R １２ , -NR １１ -C(O)NR １２ R １３ , -OCO ２ R １２ , -NR １１ -SO ２ -C １～６ alkyl, -C １～６ alkyl-OR １１ , -C １～６ alkyl-NR １１ R １２ , and -C １～６ alkyl-CO ２ R １１ and is optionally substituted as necessary. Each R １ is independently selected from the group consisting of aryl, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, and -C １～６ alkyl, and said -C １～６ alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR ａ R ｂ , -OH, -O-C １～６ alkyl, -O-C １～６ alkyl-NR ａ R ｂ , aryl, heteroaryl, and a 4- to 7-membered heterocyclic group, and said aryl, 3- to 7-membered cycloalkyl group, 4- to 7-membered heterocyclic group and heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -NR １４ R １５ , -OH, -C １～６ alkyl, -CN, -CO ２ R １４ , -CONR １４ R １５ , -SO ２ NR １４ R １５ , -SO ２ -C １～６ alkyl, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -OC(O)NR １４ R １５ , -NR １４ C(O)-C １～６ alkyl, -NR １４ C(O) ２ R １５ , -NR １４ -C(O)NR １５ R １６ , -OCO ２ R １４ and -NR １４ SO ２ -C １～６ alkyl, and is optionally substituted with 1 to 5 substituents independently selected from the group consisting of, Each R ２ 、R ３ 、R ４ 、R ５ 、R ６ 、R ７ 、R ８ 、 R ９ 、R １０ 、R １１ 、R １２ 、R １３ 、R ａ 、and R ｂ are independently selected from the group consisting of H, C １～６ alkyl, and -C １～６ alkyl-OR １４ and are selected independently from the group consisting of, -CONR ２ R ３ and -SO ２ NR ２ R ３ wherein R ２ and R ３ optionally together form a 4- to 7-membered heterocyclic group which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR ｃ R ｄ , -OH, -C １～６ alkyl, -CN, -CO ２ R １４ , -CONR １４ R １５ , -SO ２ NR １４ R １５ , -SO ２ -C １～６ alkyl, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -OC(O)NR １４ R １５ , -NR １４ C(O)-C １～６ alkyl, -NR １４ C(O) ２ R １５ , -NR １４ -C(O)NR １５ R １６ , -OCO ２ R １４ , and -NR １４ SO ２ -C １～６ alkyl and form a 4- to 7-membered heterocyclic group which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of Each R ｃ , R ｄ , R １４ , R １５ , and R １６ is independently selected from the group consisting of H and C １～６ alkyl].

2. W is H, -CH ３ or bromo, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is H or F.

4. Z is -CH ２ CH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is -CH

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II): 【Chemical 48】 or a pharmaceutically acceptable salt thereof [wherein, X is H or F, Y is H or F, A has a double bond and is -C １～６ alkyl, -COR １ -, -SO ２ R １ -, -CO ２ R ２ -, -CONR ２ R ３ -, -SO ２ NR ２ R ３ a 4- to 7-membered monocyclic heterocyclic group optionally substituted with 1 to 8 substituents independently selected from the group consisting of a 3- to 7-membered cycloalkyl group and a 4- to 7-membered heterocyclic group The foregoing -C １～６ Alkyl is -C １～６ alkyl, -NR ２ R ３ , -CN, -CO ２ R ２ , -CONR ２ R ３ , -OH, -SO ２ NR ２ R ３ , -SO ２ -C １～６ alkyl, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -OC(O)NR ２ R ３ , -NR ２ C(O)-C １～６ alkyl, -NR ２ C(O) ２ R ３ , -NR ２ -C(O)NR ３ R ４ , -OCO ２ R ３ , -NR ２ SO ２ -C １～６ alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl group, and 4- to 7-membered heterocyclic group, which are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, -C １～６ alkyl, -CN, -CO ２ R ５ , -CONR ５ R ６ , -OH, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR ５ R ６ , -OC(O)NR ５ R ６ , -NR ５ C(O)-C １～６ alkyl, -NR ５ C(O) ２ R ６ , -NR ５ -C(O)NR ６ R ７ , -C １～６ Alkyl-OR ５ , -C １～６ Alkyl-NR ５ R ６ , and -C １～６ Alkyl-CO ２ R ５ Optionally substituted with 1 to 5 substituents independently selected from the group consisting of, said aryl and heteroaryl being halogen, -CN, -CO ２ R ８ , -CONR ８ R ９ , -OH, -SH, -C １～６ Alkyl, -O-C １～６ Alkyl, -S-C １～６ Alkyl, -NR ８ R ９ , -OC(O)NR ８ R ９ , -OCO ２ R ８ , -NR ８ C(O)-C １～６ Alkyl, -NR ８ C(O) ２ R ９ , -NR ８ -C(O)NR ９ R １０ , -C １～６ Alkyl-OR ８ , -C １～６ Alkyl-NR ８ R ９ , and -C １～６ Alkyl-CO ２ R ８ Optionally substituted with 1 to 5 substituents independently selected from the group consisting of, A is a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group which may be optionally condensed or bridged, Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of spiro 3- to 7-membered cycloalkyl groups, spiro 4- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, 4- to 7-membered heterocyclic groups, -C １～６ alkyl, oxo, -CN, -CO ２ R １１ -, -CONR １１ R １２ -, -OH, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR １１ R １２ -, -OC(O)NR １１ R １２ -, -NR １１ C(O)-C １～６ alkyl, -NR １１ C(O) ２ R １２ -, -NR １１ -C(O)NR １２ R １３ -, -OCO ２ R １２ -, -NR １１ -SO ２ -C １～６ alkyl, -C １～６ alkyl-OR １１ -, -C １～６ alkyl-NR １１ R １２ -, and -C １～６ alkyl-CO ２ R １１ and are optionally substituted as needed with 1 to 5 substituents independently selected from the group consisting of Each R １ is independently selected from the group consisting of aryl, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, and -C １～６ alkyl, and the -C １～６ alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR ａ R ｂ , -OH, -O-C １～６ alkyl, aryl, and heteroaryl, and the aryl, 3- to 7-membered cycloalkyl group, 4- to 7-membered heterocyclic group, and heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, -NR １４ R １５ , -OH, -C １～６ alkyl, -CN, -CO ２ R １４ , -CONR １４ R １５ , -SO ２ NR １４ R １５ , -SO ２ -C １～６ alkyl, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -OC(O)NR １４ R １５ , -NR １４ C(O)-C １～６ alkyl, -NR １４ C(O) ２ R １５ , -NR １４ -C(O)NR １５ R １６ , -OCO ２ R １４ and -NR １４ SO ２ -C １～６ alkyl, and is optionally substituted with 1 to 5 substituents independently selected from the group consisting of Each R ２ R ３ R ４ R ５ R ６ R ７ R ８ 、 R ９ R １０ R １１ R １２ R １３ R ａ and R ｂ are independently selected from the group consisting of H and C １～６ alkyl, -CONR ２ R ３ and -SO ２ NR ２ R ３ wherein R ２ and R ３ optionally together form a 4- to 7-membered heterocyclic group which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR ｃ R ｄ , -OH, -C １～６ alkyl, -CN, -CO ２ R １４ , -CONR １４ R １５ , -SO ２ NR １４ R １５ , -SO ２ -C １～６ alkyl, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -OC(O)NR １４ R １５ , -NR １４ C(O)-C １～６ alkyl, -NR １４ C(O) ２ R １５ , -NR １４ -C(O)NR １５ R １６ , -OCO ２ R １４ , and -NR １４ SO ２ -C １～６ alkyl Each R ｃ , R ｄ , R １４ , R １５ , and R １６ is independently selected from the group consisting of H and C １～６ alkyl].

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein X is H or F, Y is H or F, and A is a 3- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group which may be optionally bridged.

7. A has a double bond and C １～６ alkyl, -COR １ , SO ２ R １ , -CO ２ R ２ , -CONR ２ R ３ , SO ２ NR ２ R ３ is a piperidine or pyrrolidine optionally substituted with 1 to 6 substituents independently selected from the group consisting of an alkyl, -COR, SO₂R, -CO₂R, -CONR₂, SO₂NR₂, a 3- to 7-membered cycloalkyl group, and a 4- to 7-membered heterocyclic group, the -C １～６ alkyl is -C １～６ alkyl, -NR ２ R ３ , -CONR ２ R ３ , -OH, -SO ２ NR ２ R ３ , -SO ２ -C １～６ alkyl, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR ２ C(O)-C １～６ alkyl, -NR ２ SO ２ -C １～６ alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl group, and 4- to 7-membered heterocyclic group, independently selected from the group consisting of 1 to 5 substituents optionally substituted, said 3- to 7-membered cycloalkyl group and said 4- to 7-membered heterocyclic group being optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, -C １～６ alkyl, and -OH, and said aryl and heteroaryl being halogen, -CN, -CO ２ R ８ , -CONR ８ R ９ , OH, SH, C １～６ alkyl, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR ８ R ９ , -OC(O)NR ８ R ９ , -NR ８ C(O)-C １～６ alkyl, -NR ８ C(O) ２ R ９ , -NR ８ -C(O)NR ９ R １０ , -OCO ２ R ８ , -C １～６ alkyl-OR ８ , -C １～６ alkyl-NR ８ R ９ , and -C １～６ Alkyl-CO ２ R ８ optionally substituted with 1 to 3 substituents independently selected from the group consisting of, The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C １～６ alkyl, oxo, and -OH, Each R １ is independently selected from the group consisting of phenyl, a 4- to 6-membered heterocyclic group, and -C １～６ alkyl, and the -C １～６ alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR ａ R ｂ , -OH, and phenyl Each R ２ , R ３ , R ８ 、 R ９ , R １０ , R ａ , and R ｂ are independently selected from the group consisting of H and C １～６ alkyl -CONR ２ R ３ and -SO ２ NR ２ R ３ wherein R ２ and R ３ optionally together form a 4- to 7-membered heterocyclic group which is optionally substituted with NR ｃ R ｄ and form a 4- to 7-membered heterocyclic group which is optionally substituted as required, Each R ｃ and R ｄ are each independently selected from the group consisting of H and C １～６ alkyl

8. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of

9. 【Chemical 49】 The compound according to claim 8 or a pharmaceutically acceptable salt thereof, which is independently selected from the group consisting of Each of these is -CO ２ R ｙ , -CONR ｙ R ｚ , and -C １～６ One to three Rs independently selected from the group consisting of alkyl are optionally substituted, and said -C ｘ alkyl is optionally substituted with one to five substituents independently selected from the group consisting of -CN, -OH, -O-C １～６ alkyl, -CO １～６ R ２ , and -CONR ｙ R ｙ ｚ and is optionally substituted as needed,​ R is H, -C １～６ alkyl, -COR １ , -SO ２ R １ , -CO ２ R ２ , -CONR ２ R ３ , -SO ２ NR ２ R ３ selected from the group consisting of a 3- to 7-membered cycloalkyl group and a 4- to 7-membered heterocyclic group, Said C １～６ alkyl is -C １～６ alkyl, -NR ２ R ３ , -CN, -CO ２ R ２ , -CONR ２ R ３ , OH, -SO ２ NR ２ R ３ , SO ２ -C １～６ alkyl, SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -OC(O)NR ２ R ３ , -NR ２ C(O)-C １～６ alkyl, -NR ２ C(O) ２ R ３ , -NR ２ -C(O)NR ３ R ４ , -OCO ２ R ２ , -NR ２ SO ２ -C １～６ alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl group, and 4- to 7-membered heterocyclic group, independently selected from the group consisting of 1 to 5 substituents optionally substituted, wherein said 3- to 7-membered cycloalkyl group and said 4- to 7-membered heterocyclic group are oxo, -C １～６ alkyl, -CN, -CO ２ R ５ , -CONR ５ R ６ , -OH, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR ５ R ６ , -OC(O)NR ５ R ６ , -NR ５ C(O)-C １～６ alkyl, -NR ５ C(O) ２ R ６ , -NR ５ -C(O)NR ６ R ７ , -OCO ２ R ５ 、 - C １～６ alkyl - OR ５ 、 - C １～６ alkyl - NR ５ R ６ 、 and - C １～６ alkyl - CO ２ R ５ selected independently from the group consisting of 1 to 5 substituents, optionally substituted, wherein said aryl and heteroaryl are halogen, - CN, - CO ２ R ８ 、 - CONR ８ R ９ 、 - OH, - SH, - C １～６ alkyl, - O - C １～６ alkyl, - S - C １～６ alkyl, - NR ８ R ９ 、 - OC(O)NR ８ R ９ 、 - NR ８ C(O) - C １～６ alkyl, - NR ８ C(O) ２ R ９ 、 - NR ８ - C(O)NR ９ R １０ 、 - OCO ２ R ８ 、 - C １～６ alkyl - OR ８ 、 - C １～６ alkyl - NR ８ R ９ 、 and - C １～６ alkyl - CO ２ R ８ selected independently from the group consisting of 1 to 5 substituents, optionally substituted, Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group are independently selected from the group consisting of a spiro 3- to 7-membered cycloalkyl group, a spiro 4- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, -C １～６ alkyl, oxo, -CN, -CO ２ R １１ -, -CONR １１ R １２ -, -OH, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR １１ R １２ -, -OC(O)NR １１ R １２ -, -NR １１ C(O)-C １～６ alkyl, -NR １１ C(O) ２ R １２ -, -NR １１ -C(O)NR １２ R １３ -, -OCO ２ R １１ -, -NR １１ -SO ２ -C １～６ alkyl, -C １～６ alkyl-OR １１ -, -C １～６ alkyl-NR １１ R １２ -, and -C １～６ alkyl-CO ２ R １１ and are optionally substituted with 1 to 5 substituents independently selected from the group consisting of: Each R １ is independently selected from the group consisting of aryl, a 3- to 7-membered cycloalkyl group, a 4- to 7-membered heterocyclic group, and -C １～６ alkyl, and the -C １～６ alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR ａ R ｂ , -OH, -O-C １～６ alkyl, aryl, and heteroaryl, and the aryl, 3- to 7-membered cycloalkyl group, 4- to 7-membered heterocyclic group, and heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR １４ R １５ , -OH, -C １～６ alkyl, -CN, -CO ２ R １４ , -CONR １４ R １５ , -SO ２ NR １４ R １５ , -SO ２ -C １～６ alkyl, -SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -OC(O)NR １４ R １５ , -NR １４ C(O)-C １～６ alkyl, -NR １４ C(O) ２ R １５ , -NR １４ -C(O)NR １５ R １６ , -OCO ２ R １４ , and -NR １４ SO ２ -C １～６ alkyl, and is optionally substituted with 1 to 5 substituents independently selected from the group consisting of, Each R ２ 、R ３ 、R ４ 、R ５ 、R ６ 、R ７ 、R ８ 、 R ９ 、R １０ 、R １１ 、R １２ 、R １３ 、R １４ 、R １５ 、R １６ 、R ａ 、R ｂ 、R ｃ 、R ｄ 、R ｙ 、and R ｚ are independently selected from the group consisting of H and C １～６ alkyl, -CONR ｙ R ｚ wherein R ｙ and R ｚ optionally together form, with NR ｃ R ｄ , OH, -C １～６ alkyl, CN, -CO ２ R １４ , -CONR １４ R １５ , -SO ２ NR １４ R １５ , SO ２ -C １～６ alkyl, SH, -O-C １～６ alkyl, -S-C １～６ alkyl, -OC(O)NR １４ R １５ , -NR １４ C(O)-C １～６ alkyl, -NR １４ C(O) ２ R １５ , -NR １４ -C(O)NR １５ R １６ , -OCO ２ R １４ , and -NR １４ SO ２ -C １～６ alkyl, and form a 4- to 7-membered heterocyclic group optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

10. The compound according to claim 7 or a pharmaceutically acceptable salt thereof.

11. 【Chemical Formula 50】 The compound according to claim 10 or a pharmaceutically acceptable salt thereof. Each of these is optionally substituted with 1 to 3 Rs ｘ and each R ｘ is independently —OH, —OC １～３ alkyl, —CN, —CO ２ —C １～３ alkyl, and —CONR ｙ R ｚ and is optionally substituted with —C １～３ alkyl, where R ｙ and R ｚ are each independently selected from C １～３ alkyl, and R ｙ and R ｚ optionally combine together to form a 4- to 6-membered heterocyclic group optionally substituted with NR ｃ R ｄ and R ｃ and R ｄ are each independently selected from the group consisting of H and C １～３ alkyl, the compound according to claim 7 or a pharmaceutically acceptable salt thereof.

12. Each R ｘ is Me, -CH ２ OH, -CH ２ OMe, -CH ２ CN, -CH ２ CONMe ２ 、-CH ２ CO ２ Me, -CO ２ Me, and 【Chemical 51】 The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein Y is H and A is selected from the group consisting of

13. R is H, -C １～６ alkyl, -COR １ , -SO ２ R １ , -CO ２ R ２ , -CONR ２ R ３ , -SO ２ NR ２ R ３ selected from the group consisting of a 3- to 7-membered cycloalkyl group and a 4- to 7-membered heterocyclic group, the foregoing -C １～６ alkyl is -C １～６ alkyl, -NR ２ R ３ , -CONR ２ R ３ , -OH, -SO ２ NR ２ R ３ , -SO ２ -C １～６ alkyl, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR ２ C(O)-C １～６ alkyl, -NR ２ SO ２ -C １～６ alkyl, aryl, heteroaryl, 3- to 7-membered cycloalkyl group, and 4- to 7-membered heterocyclic group, independently selected from the group consisting of 1 to 5 substituents, optionally substituted, said 3- to 7-membered cycloalkyl group and said 4- to 7-membered heterocyclic group being optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, -C １～６ alkyl, and -OH, and said aryl and heteroaryl being halogen, -CN, -CO ２ R ８ , -CONR ８ R ９ , OH, SH, C １～６ alkyl, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR ８ R ９ , -OC(O)NR ８ R ９ , -NR ８ C(O)-C １～６ alkyl, -NR ８ C(O) ２ -C １～６ alkyl, -NR ８ , -NR ９ R １０ , -OCO ２ R ８ , -C １～６ alkyl-OR ８ , -C １～６ alkyl-NR ８ R ９ , and -C １～６ alkyl-CO ２ R ８ optionally substituted with 1 to 5 substituents independently selected from the group consisting of; Each 3- to 7-membered cycloalkyl group and each 4- to 7-membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C １～６ alkyl, oxo, and -OH, Each R １ is independently selected from the group consisting of aryl, a 4- to 7-membered heterocyclic group, and -C １～６ alkyl, and the -C １～６ alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR ａ R ｂ , -OH, and aryl Each R ２ , R ３ , R ８ 、 R ９ , R １０ , R ａ , and R ｂ are independently selected from the group consisting of H and C １～６ alkyl, The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein Y is H and A is selected from the group consisting of

14. R is H, -C １～６ alkyl, -COR １ , -SO ２ R １ , -CO ２ R ２ , -CONR ２ R ３ , -SO ２ NR ２ R ３ selected from the group consisting of a 4- to 6-membered cycloalkyl group and a 4- to 6-membered heterocyclic group, The above - C １～６ wherein the alkyl is - NR ２ R ３ -, - CONR ２ R ３ -, - OH, - SO ２ NR ２ R ３ -, - SO ２ -C １～６ alkyl, - O - C １～６ alkyl, - S - C １～６ alkyl, - NR ２ C(O)-C １～６ alkyl, - NR ２ SO ２ -C １～６ alkyl, phenyl, 5 - membered heteroaryl, 4 - to 6 - membered cycloalkyl group, and 4 - to 6 - membered heterocyclic group, and is optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo and - OH, and the 4 - to 6 - membered cycloalkyl group and the 4 - to 6 - membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo and - OH, The 4- to 6-membered cycloalkyl group and the 4- to 6-membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C １～６ alkyl, oxo, and -OH, Each R １ is independently selected from the group consisting of phenyl, a 4- to 6-membered heterocyclic group, and -C １～６ alkyl, and the -C １～６ alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR ａ R ｂ , -OH, and phenyl, Each R ２ , R ３ , R ａ , and R ｂ is independently selected from the group consisting of H and C １～６ alkyl. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein Y is H.

15. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein Y is F. 【Chemical 52】

16. Each of these is optionally substituted with 1 to 3 Rs ｘ and each R ｘ is independently —OH, —OC １～３ alkyl, —CN, —CO ２ —C １～３ alkyl, and —CONR ｙ R ｚ optionally substituted with —C １～３ alkyl, where R ｙ and R ｚ are each independently selected from C １～３ alkyl, R ｙ and R ｚ optionally combine together to form a 4- to 6-membered heterocyclic group optionally substituted with NR ｃ R ｄ and R ｃ and R ｄ are each independently selected from the group consisting of H and C １～３ alkyl, R is H, -C １～６ alkyl, -COR １ , -SO ２ R １ , -CO ２ R ２ , -CONR ２ R ３ , -SO ２ NR ２ R ３ selected from the group consisting of a 3- to 7-membered cycloalkyl group and a 4- to 7-membered heterocyclic group, The above - C １～６ wherein the alkyl is - C １～６ alkyl, - NR ２ R ３ , - CONR ２ R ３ , - OH, - SO ２ NR ２ R ３ , - SO ２ - C １～６ alkyl, - O - C １～６ alkyl, - S - C １～６ alkyl, - NR ２ C(O) - C １～６ alkyl, - NR ２ SO ２ - C １～６ alkyl, aryl, heteroaryl, 3 - to 7 - membered cycloalkyl group, and 4 - to 7 - membered heterocyclic group, independently selected from the group consisting of 1 to 5 substituents which are optionally substituted, wherein the 3 - to 7 - membered cycloalkyl group and the 4 - to 7 - membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, - C １～６ alkyl, and - OH, and the aryl and heteroaryl are halogen, - CN, - CO ２ R ８ , - CONR ８ R ９ , OH, SH, C １～６ alkyl, - O - C １～６ alkyl, - S - C １～６ alkyl, - NR ８ R ９ , - OC(O)NR ８ R ９ , - NR ８ C(O) - C １～６ alkyl, - NR ８ C(O) ２ - C １～６ alkyl, - NR ８ , - NR ９ R １０ , - OCO ２ R ８ , - C １～６ alkyl - OR ８ , - C １～６ alkyl - NR ８ R ９ , and -C １～６ alkyl-CO ２ R ８ optionally substituted with 1 to 5 substituents independently selected from the group consisting of; The 3- to 7-membered cycloalkyl group and the 4- to 7-membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C １～６ alkyl, oxo, and -OH. Each R １ is independently selected from the group consisting of aryl, a 4- to 7-membered heterocyclic group, and -C １～６ alkyl, and the -C １～６ alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR ａ R ｂ , -OH, and aryl. Each R ２ 、R ３ 、R ８ 、 R ９ 、R １０ 、R ａ 、and R ｂ are independently selected from the group consisting of H and C １～６ alkyl, The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein X is H.

17. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein X is F. 【Chemical 53】

18. Each of these is Me, -CH ２ OH, -CH ２ OMe, -CH ２ CN, -CH ２ CONMe ２ , -CH ２ CO ２ Me, -CO ２ Me, and 【Chemical 54】 1 to 3 Rs independently selected from the group consisting of ｘ optionally substituted with R is H, -C １～６ alkyl, -COR １ , -SO ２ R １ , -CO ２ R ２ , -CONR ２ R ３ , -SO ２ NR ２ R ３ selected from the group consisting of a 4- to 6-membered cycloalkyl group and a 4- to 6-membered heterocyclic group, The foregoing -C １～６ wherein alkyl is -NR ２ R ３ -, -CONR ２ R ３ -, -OH, -SO ２ NR ２ R ３ -, -SO ２ -C １～６ alkyl, -O-C １～６ alkyl, -S-C １～６ alkyl, -NR ２ C(O)-C １～６ alkyl, -NR ２ SO ２ -C １～６ alkyl, phenyl, 5-membered heteroaryl, 4-6 membered cycloalkyl group, and 4-6 membered heterocyclic group, and is optionally substituted with 1 to 5 substituents independently selected from the group consisting of, and the 4-6 membered cycloalkyl group and the 4-6 membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo and -OH. The 4- to 6-membered cycloalkyl group and the 4- to 6-membered heterocyclic group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of -C １～６ alkyl, oxo, and -OH. Each R １ is independently selected from the group consisting of phenyl, a 4- to 6-membered heterocyclic group, and -C １～６ alkyl, and the -C １～６ alkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -NR ａ R ｂ , -OH, and phenyl Each R ２ , R ３ , R ａ , and R ｂ is independently selected from the group consisting of H and C １～６ alkyl, A compound of formula 1: or a pharmaceutically acceptable salt thereof.

19. A compound of formula 2: or a pharmaceutically acceptable salt thereof.

20. A compound of formula 3: or a pharmaceutically acceptable salt thereof.

21. A compound selected from Table 4 or a pharmaceutically acceptable salt thereof. ​ 【Chemical Formula 55】 ​ ​ ​ 【Chemical Formula 56】 ​ ​ ​ 【Chemical 57】 ​ ​ ​

22. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. The pharmaceutical composition according to claim 22, further comprising one or more other therapeutic agents.

24. A composition for treating a respiratory disease in a human in need of treatment for a respiratory disease, the composition comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

25. The composition according to claim 24, wherein the respiratory disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, sarcoidosis, eosinophilic diseases, helminth infections, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung diseases, drug-induced pneumonia, fungal-induced pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, eosinophilic syndrome, Reffler syndrome, bronchiolitis obliterans organizing pneumonia, lung transplant rejection, COVID-19, SARS, MERS, chronic rhinosinusitis with or without nasal polyps, nasal polyposis, rhinosinusitis with nasal polyps, rhinitis, and immune checkpoint inhibitor-induced pneumonia.

26. The composition according to claim 25, wherein the respiratory disease is asthma.

27. The composition according to claim 26, wherein the respiratory disease is chronic obstructive pulmonary disease.

28. A composition for treating lung transplant rejection in a human in need of treatment for lung transplant rejection, the composition comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

29. The composition according to claim 28, wherein the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic allograft dysfunction.

30. The composition according to claim 28, wherein the lung transplant rejection is acute lung transplant rejection.

31. The composition according to claim 28, wherein the lung transplant rejection is chronic allograft dysfunction.

32. The composition according to claim 28, wherein the lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic allograft lung dysfunction, and neutrophilic allograft dysfunction.

33. A composition for use in therapy, comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

34. A composition for use in treating a respiratory disease, comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

35. Use of the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a respiratory disease.

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